Producing Calcium Phosphate Compositions

ABSTRACT

The disclosure features compositions that include a material featuring three calcium phosphate phases that form one or more integral units of a solid, where a first one of the three phases includes one or more regions formed of hydroxyapatite, a second one of the three phases includes one or more regions formed of β-tricalcium phosphate, a third one of the three phases includes one or more regions formed of amorphous calcium phosphate, and where at least some of the regions corresponding to the first, second, and third phases contact one another in the one or more integral units of the solid.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to the following U.S. Provisionalpatent applications, the entire contents of each of which areincorporated herein by reference: 62/232,961, filed on Sep. 25, 2015;62/232,999, filed on Sep. 25, 2015; and 62/246,796, filed on Oct. 27,2015.

TECHNICAL FIELD

This disclosure relates to calcium phosphate compositions and methodsfor producing such compositions.

BACKGROUND

Calcium phosphates are a family of compounds that include calcium (II)and orthophosphate ions. Other ions such as hydroxide ions can also bepresent. Calcium phosphates are important industrial materials and areused for a variety of applications including fertilizer production,baking, nutritional supplementation, dentistry, and medicine.

SUMMARY

Calcium phosphate compounds can be obtained through direct recoveryoperations and industrial manufacturing. Direct recovery operations suchas mining present significant challenges. Among these are the difficultyof locating and recovering calcium phosphate compounds of desiredcomposition, since calcium phosphates vary in composition. Otherdifficulties including refining recovered products to reduce impurities,which are present in virtually all naturally occurred calcium phosphatesources.

Conventional industrial methods of production are also limited in anumber of ways. While calcium phosphate compositions can be producedwith a certain range of variability in composition, exertingreproducible control over a wide range of compositions is difficult.Furthermore, conventional industrial processes rely on large volumes ofreagents, some of which are relatively expensive, to produce usefulproducts. Furthermore, conditions that are used to manufacture certaintypes of economically valuable calcium phosphate compounds such ashydroxyapatite yield products at high economic cost.

This disclosure features methods for controlled, low cost production ofa wide variety of calcium phosphate compositions in a relativelystraightforward production process. The methods can be variedsystematically to yield products with predictable composition. Inaddition, the methods can be adjusted to yield products with controlledvariation in physical properties such as specific surface area,crystallinity, and particle size. Accordingly, the methods disclosedherein provide for economically feasible and controllable synthesis of awide variety of calcium phosphate compositions on an industrial scale.

In general, in a first aspect, the disclosure features methods thatinclude obtaining a first plurality of particles that include calciumcarbonate, where the particles have a distribution of sizes between 8 mmand 12 mm, and heating the first plurality of particles to a temperatureof between 900° C. and 1200° C. for a time period of at least 1 hour togenerate a second plurality of particles that include calcium oxide.

Embodiments of the methods can include any one or more of the followingfeatures.

An average maximum dimension of the particles can be about 10 mm, and afull width at half maximum of a distribution of the maximum dimension ofthe particles can be 4 mm or less. A concentration of calcium carbonatein the first plurality of particles can be at least 94% (e.g., at least98%). A concentration of calcium carbonate in the second plurality ofparticles can be less than 0.5% (e.g., less than 0.1%).

An efficiency of conversion of calcium carbonate in the first pluralityof particles to calcium oxide in the second plurality of particles canbe 95% or greater (e.g., 99% or greater). The first plurality ofparticles can be heated to a temperature of between 1100° C. and 1200°C. (e.g., to a temperature of greater than 1000° C.) to generate thesecond plurality of particles.

The methods can include increasing the temperature to which the firstplurality of particles are heated during the time period. The methodscan include increasing the temperature in a sequence of steps during thetime period, where at each successive step, the first plurality ofparticles are heated at a constant temperature that is higher than atemperature of an immediately preceding step, for a portion of the timeperiod. The sequence of steps can include at least three steps, where afirst step in the sequence includes heating the first plurality ofparticles to a temperature of between 900° C. and 1000° C., a secondstep in the sequence includes heating the first plurality of particlesto a temperature of between 1000° C. and 1100° C., and a third step inthe sequence includes heating the first plurality of particles to atemperature of between 1100° C. and 1200° C.

The methods can include continuously increasing the temperature to whichthe first plurality of particles are heated during the time period. Themethods can include increasing the temperature linearly between a firsttemperature of between 900° C. and 1000° C., and a second temperature ofbetween 1100° C. and 1200° C.

The time period can be between 1 hour and 2 hours (e.g., between 2 hoursand 3 hours).

The full width at half maximum of the distribution of the maximumdimension of the first plurality of particles can be 3 mm or less (e.g.,2 mm or less). A specific surface area of the second plurality ofparticles can be at least 10.0 m²/g. A specific porosity of the secondplurality of particles can be at least 15.0 cm³/g.

Embodiments of the methods can also include any of the other featuresdisclosed herein, including features disclosed in connection withdifferent embodiments, in any combination except as specifically stated.

In another aspect, the disclosure features compositions that include aplurality of particles having an average maximum dimension of between 8mm and 12 mm and featuring a calcium oxide concentration of at least99%, where a surface area of the particles is at least 10.0 m²/g and aspecific porosity of the particles is at least 15.0 cm³/g.

Embodiments of the compositions can include any one or more of thefollowing features.

The surface area of the particles can be at least 14.0 m²/g (e.g., atleast 20.0 m²/g). The specific porosity of the particles can be at least20.0 cm³/g (e.g., at least 30.0 cm³/g).

Embodiments of the compositions can also include any of the otherfeatures disclosed herein, including features disclosed in connectionwith different embodiments, in any combination except as specificallystated.

In a further aspect, the disclosure features methods that includeobtaining a first calcium hydroxide solution featuring a firstconcentration of calcium ions and a second calcium hydroxide solutionfeaturing a second concentration of calcium ions, adding a phosphoricacid solution to the first calcium hydroxide solution to generate acombined solution that includes an aqueous suspension of calciumdihydrogen phosphate particles, and adding the second calcium hydroxidesolution to the combined solution to form a product solution thatincludes an aqueous suspension of particles of a calcium phosphatematerial.

Embodiments of the methods can include any one or more of the followingfeatures.

The first and second concentrations of calcium ions can be different.

Obtaining the first calcium hydroxide solution can include combining afirst plurality of particles comprising calcium oxide with water, wherethe particles have a specific surface area of at least 10.0 m²/g.Obtaining the second calcium hydroxide solution can include combining asecond plurality of the particles with water. The particles can have aspecific porosity of at least 15.0 cm³/g.

The methods can include adding the phosphoric acid solution to the firstcalcium hydroxide solution until a pH of the combined solution isbetween 1 and 2. The pH of the combined solution can be about 1.66.

The methods can include adding the phosphoric acid solution to the firstcalcium hydroxide solution in three portions, where after addition of afirst one of the three portions, a pH of the first calcium hydroxidesolution is between 8.5 and 9.5. Combining the first calcium hydroxidesolution and the first portion of the phosphoric acid solution can forma first buffer solution of phosphate ions and biphosphate ions.

After addition of a second one of the three portions, the pH of thefirst calcium hydroxide solution can be between 3.5 and 4.5. Combiningthe first calcium hydroxide solution and the first and second portionsof the phosphoric acid solution can form a second buffer solution ofbiphosphate ions and dihydrogen phosphate ions.

A pH of the product solution can be between 6.5 and 7.5. The pH of theproduct solution can be between 11.5 and 12.5.

The methods can include separating the calcium phosphate material fromthe product solution, and heating the calcium phosphate material to atemperature of at least 700° C. (e.g., at least 800° C., at least 900°C.) for a time period of at least 1 hour (e.g., between 1.5 hours and2.5 hours).

The methods can include subjecting the calcium phosphate material to athermal shock treatment by increasing a temperature of the calciumphosphate material by at least 450° C. during a time period of less than15 minutes to expel water vapor from the calcium phosphate material.

The calcium phosphate material can include two phases, eachcorresponding to a different calcium phosphate compound. A first one ofthe phases can correspond to hydroxyapatite and a second one of thephases can correspond to β-tricalcium phosphate. A first one of thephases can correspond to hydroxyapatite and a second one of the phasescan correspond to amorphous calcium phosphate. A first one of the phasescan correspond to β-tricalcium phosphate and a second one of the phasescan correspond to amorphous calcium phosphate.

The calcium phosphate material can include three phases, eachcorresponding to a different calcium phosphate compound. A first one ofthe phases can correspond to hydroxyapatite, a second one of the phasescan correspond to β-tricalcium phosphate, and a third one of the phasescan correspond to amorphous calcium phosphate. A first one of the phasescan correspond to calcium hydrogen phosphate dihydrate, a second one ofthe phases can correspond to anhydrous calcium hydrogen phosphate, and athird one of the phases can correspond to β-tricalcium phosphatemonohydrate.

The particles of the calcium phosphate material can have a crystallinityof 80% or more (e.g., 95% or more). The particles of the calciumphosphate material can have a specific surface area of 60 m²/g or more(e.g., 80 m²/g or more).

Embodiments of the methods can also include any of the other featuresdisclosed herein, including features disclosed in connection withdifferent embodiments, in any combination except as specifically stated.

In another aspect, the disclosure features compositions that include amaterial featuring three calcium phosphate phases that form one or moreintegral units of a solid, where a first one of the three phasesfeatures one or more regions formed of hydroxyapatite, where a secondone of the three phases features one or more regions formed ofβ-tricalcium phosphate, where a third one of the three phases featuresone or more regions formed of amorphous calcium phosphate, and where atleast some of the regions corresponding to the first, second, and thirdphases contact one another in the one or more integral units of thesolid.

Embodiments of the compositions can include any one or more of thefollowing features.

A concentration percentage of the hydroxyapatite in the composition canbe between 5% and 95% (e.g., between 20% and 80%). A concentrationpercentage of the β-tricalcium phosphate in the composition can bebetween 10% and 80% (e.g., between 20% and 60%). A concentrationpercentage of the amorphous calcium phosphate can be between 10% and 80%(e.g., between 20% and 60%).

A crystallinity of the material can be at least 90% (e.g., at least95%). A specific surface area of the material can be at least 50 m²/g(e.g., at least 70 m²/g). A specific porosity of the material can be atleast 25 cm³/g (e.g., at least 30 cm³/g).

The one or more integral units can include particles, where an averagemaximum dimension of the particles can be between 100 nm and 500 nm, andwhere an average aspect ratio of the particles can be 50:1 or more. Theaverage aspect ratio of the particles can be 100:1 or more.

Embodiments of the compositions can also include any of the otherfeatures disclosed herein, including features disclosed in connectionwith different embodiments, in any combination except as specificallystated.

In a further aspect, the disclosure features compositions that include amaterial featuring three calcium phosphate phases that form one or moreintegral units of a solid, where a first one of the three phasesfeatures one or more regions formed of hydroxyapatite, where a secondone of the three phases features one or more regions formed of calciumhydrogen phosphate dihydrate, where a third one of the three phasesfeatures one or more regions formed of anhydrous calcium hydrogenphosphate, and where at least some of the regions corresponding to thefirst, second, and third phases contact one another in the one or moreintegral units of the solid.

Embodiments of the compositions can include any one or more of thefollowing features.

A concentration percentage of the hydroxyapatite in the composition canbe between 10% and 60% (e.g., between 20% and 50%). A concentrationpercentage of the calcium hydrogen phosphate dihydrate in thecomposition can be between 10% and 75% (e.g., between 20% and 60%). Aconcentration percentage of the anhydrous calcium hydrogen phosphate canbe between 5% and 70% (e.g., between 10% and 60%).

A crystallinity of the material can be at least 90% (e.g., at least95%). A specific surface area of the material can be at least 50 m²/g(e.g., at least 70 m²/g). A specific porosity of the material can be atleast 25 cm³/g (e.g., at least 30 cm³/g).

The one or more integral units can include particles, where an averagemaximum dimension of the particles can be between 100 nm and 500 nm, andwhere an average aspect ratio of the particles can be 50:1 or more. Theaverage aspect ratio of the particles can be 100:1 or more.

Embodiments of the compositions can also include any of the otherfeatures disclosed herein, including features disclosed in connectionwith different embodiments, in any combination except as specificallystated.

In another aspect, the disclosure features compositions that include amaterial featuring two calcium phosphate phases that form one or moreintegral units of a solid, where a first one of the two phases includesone or more regions formed of hydroxyapatite, where a second one of thethree phases includes one or more regions formed of β-tricalciumphosphate, and where at least some of the regions corresponding to thefirst and second phases contact one another in the one or more integralunits of the solid.

Embodiments of the compositions can include any one or more of thefollowing features.

A concentration percentage of the hydroxyapatite in the composition canbe between 8% and 95% (e.g., between 20% and 80%). A concentrationpercentage of the β-tricalcium phosphate in the composition can bebetween 5% and 92% (e.g., between 20% and 80%).

A crystallinity of the material can be at least 90% (e.g., at least95%). A specific surface area of the material can be at least 50 m²/g(e.g., at least 70 m²/g). A specific porosity of the material can be atleast 25 cm³/g (e.g., at least 30 cm³/g).

The one or more integral units can include particles, where an averagemaximum dimension of the particles can be between 100 nm and 500 nm, andwhere an average aspect ratio of the particles can be 50:1 or more. Theaverage aspect ratio of the particles can be 100:1 or more.

Embodiments of the compositions can also include any of the otherfeatures disclosed herein, including features disclosed in connectionwith different embodiments, in any combination except as specificallystated.

In a further aspect, the disclosure features compositions that include aplurality of particles formed of hydroxyapatite, where an averagemaximum dimension of the particles is between 100 nm and 500 nm, anaverage aspect ratio of the particles is 50:1 or more, and a specificsurface area of the particles is 70 m²/g or more.

Embodiments of the compositions can include any one or more of thefollowing features.

The average maximum dimension of the particles can be between 150 nm and400 nm (e.g., between 200 nm and 400 nm, between 200 nm and 350 nm). Theaverage aspect ratio of the particles can be 75:1 or more (e.g., 100:1or more, 150:1 or more, 200:1 or more).

The specific surface area of the particles can be 75 m²/g or more (e.g.,80 m²/g or more, 85 m²/g or more). A crystallinity of the particles canbe 85% or more (e.g., 90% or more, 95% or more).

Embodiments of the compositions can also include any of the otherfeatures disclosed herein, including features disclosed in connectionwith different embodiments, in any combination except as specificallystated.

Definitions

As used herein, the terms “about” and “approximately” are usedinterchangeably, and ‘when used to modify a numerical value, encompass arange of ±10% of the numerical value.

As used herein, the term “morphology” refers to the structure ordistribution of atoms in a chemical compound. For example, morphologycan refer to the crystal structure or the microstructure of a material,the spatial distribution of different compositional phases within amaterial, and/or other variations in structure within a material.

As used herein, the term “calcium oxide” refers to a compound having thenominal chemical formula CaO. The term “calcium oxide” refers to solidCaO, to solvated CaO (i.e., CaO dissolved in a solvent such as water),and to particles that include CaO and are suspended or otherwisedispersed in a fluid. In some embodiments, a calcium oxide, as discussedherein, can be a reactive calcium oxide (and may be referred to hereinas a “reactive calcium oxide”).

As used herein, the term “calcium hydroxide” refers to a compound havingthe nominal chemical formula Ca(OH)₂. The term “calcium hydroxide”refers to solid Ca(OH)₂, to solvated Ca(OH)₂ (i.e., Ca(OH)₂ dissolved ina solvent such as water), and to particles that include Ca(OH)₂ and aresuspended or otherwise dispersed in a fluid.

As used herein, the term “calcium phosphate composition” refers to acomposition that includes one or more calcium phosphate compounds.

As used herein, the terms “calcium phosphate,” “calcium phosphatecompound,” and “calcium phosphate material” refer to a substance with achemical formula that includes at least one calcium (II) ion and one ormore of an orthophosphate ion, a metaphosphate ion, and a pyrophosphateion. Some or all of these ions can also be present in combination withincalcium phosphates, calcium phosphate compounds, and calcium phosphatematerials.

As used herein, the term “orthophosphate ion” refers to a PO₃ ³⁻ anionof the following chemical structure:

As used herein, the term “metaphosphate ion” refers to a P₃O₉ ⁻ anion ofthe following chemical structure:

As used herein, the term “pyrophosphate ion” refers to a P₂O₇ ⁴⁻ anionof the following chemical structure:

As used herein, the term “amorphous calcium phosphate (ACP)” refers tocalcium phosphate compound having the chemical formula Ca₃(PO₄)₂.nH₂O,and characterized by a substantial lack of periodicity in thedistribution of atoms or ions within the compound. The Ca:P ratio in ACPis 1.5:1.

As used herein, the term “β-tricalcium phosphate (β-TCP)” refers to acalcium phosphate compound having the chemical formula Ca₃(PO₄)₂. Insome embodiments, β-TCP compounds have a rhombohedral crystal structure.The Ca:P ratio in β-TCP is 1.5:1.

As used herein, the term “β-tricalcium phosphate monohydrate (β-TCPM)”refers to a calcium phosphate compound having the chemical formulaCa₃(PO₄)₂.H₂O, for which the Ca:P ratio is 1.5:1.

As used herein, the term “hydroxyapatite (HA)” refers to calciumphosphate compound having the chemical formula Ca₁₀(PO₄)₆(OH)₂. In someembodiments, hydroxyapatite compounds have a hexagonal crystalstructure. The Ca:P ratio in HA is 1.67:1.

As used herein, the term “tetracalcium phosphate” refers to a calciumphosphate compound having the chemical formula Ca₄O(PO₄)₂, for which theCa:P ratio is 2:1.

As used herein, the term “α-tricalcium phosphate (α-TCP)” refers to acalcium phosphate compound having the chemical formula Ca₃(PO₄)₂. TheCa:P ratio in α-TCP is 1.5:1.

As used herein, the term “α′-tricalcium phosphate (α′-TCP)” refers to acalcium phosphate compound having the chemical formula Ca₃(PO₄)₂. TheCa:P ratio in α′-TCP is 1.5:1.

As used herein, the term “γ-tricalcium phosphate (γ-TCP)” refers to acalcium phosphate compound having the chemical formula Ca₃(PO₄)₂. TheCa:P ratio in γ-TCP is 1.5:1.

As used herein, the term “octacalcium phosphate (OCP)” refers to acalcium phosphate compound having the chemical formula Ca₈H₂(PO₄)₆.5H₂O,for which the Ca:P ratio is 1.33:1.

As used herein, the term “calcium hydrogen phosphate dihydrate (DCPD)”refers to a calcium phosphate compound having the chemical formulaCaHPO₄.2H₂O, for which the Ca:P ratio is 1:1.

As used herein, the terms “calcium hydrogen phosphate”, “monetite”, and“anhydrous calcium hydrogen phosphate (DCPA)” refer to a calciumphosphate compound having the chemical formula CaHPO₄, for which theCa:P ratio is 1:1.

As used herein, the term “calcium pyrophosphate (CPP)” refers to acalcium phosphate compound having the chemical formula Ca₂P₂O₇, forwhich the Ca:P ratio is 1:1.

As used herein, the term “calcium pyrophosphate dihydrate (CPPD)” refersto a calcium phosphate compound having the chemical formulaCa₂P₂O₇.2H₂O, for which the Ca:P ratio is 1.1.

As used herein, the term “heptacalcium phosphate (HCP)” refers to acalcium phosphate compound having the chemical formula Ca₇(P₅O₁₆)₂, forwhich the Ca:P ratio is 0.7:1.

As used herein, the term “tetracalcium dihydrogen phosphate (TDHP)”refers to a calcium phosphate compound having the chemical formulaCa₄H₂P₆O₂₀, for which the Ca:P ratio is 0.67:1.

As used herein, the term “calcium dihydrogen phosphate monohydrate”refers to a calcium phosphate compound having the chemical formulaCa(H₂PO₄).H₂O, for which the Ca:P ratio is 0.5:1.

As used herein, the terms “α-calcium metaphosphate (α-CMP)”, “β-calciummetaphosphate (β-CMP)”, and “γ-calcium metaphosphate (γ-CMP)” refer todifferent calcium phosphate compounds, each having the same chemicalformula Ca(PO₃)₂, for which the Ca:P ratio is 0.5:1.

The calcium phosphate compositions disclosed herein can include one ormore phases. As used herein, the term “phase” refers to a calciumphosphate compound within the calcium phosphate composition. In someembodiments, different phases within a composition are distributed indifferent spatial regions of the composition, so that the compositionfeatures distinct spatial regions corresponding to individual calciumphosphate compounds. The different spatial regions can be separated, incontact with another, and otherwise distributed in a variety ways, butgenerally form one or more integral units (such as particles) of asolid. For example, phases within a calcium phosphate composition canform separate domains within the composition. In certain embodiments,the domains can be of different sizes and have other properties thatdiffer in addition to chemical composition (e.g., the domains can differin crystallinity, melting point, surface structure, specific surfacearea, and other physical properties). The term “monophasic” refers to acomposition with only a single phase therein; “biphasic” and “triphasic”refer to compositions with two and three phases, respectively.“Multiphasic” refers to compositions with two or more phases. In allcompositions with two or more phases, the composition can includemultiple domains corresponding to each phase. For example, a compositionwith multiple regions corresponding to a first phase (i.e., a firstcalcium phosphate compound) and multiple regions corresponding to asecond phase (i.e., a second calcium phosphate compound), and no othercalcium phosphate compounds, would be a biphasic composition.

As used herein, the term “crystallinity” of a material is the portion ofthe material that is in a crystalline state, i.e., having some longrange ordering at the atomic level. The crystallinity of a material canbe measured from the material's powder x-ray diffraction peaks bycomparing the peak widths to standard peak widths and using Rietveldrefinement to quantify the crystallinity of the material. Thecrystallinity is a number between 0% and 100%.

As used herein, the term “specific surface area” of a material is thetotal surface area of the material per unit of mass. The specificsurface area can be determined by measuring nitrogen adsorption on thesurface area of the material using the Brunauer-Emmett-Teller (BET)method.

As used herein, the term “specific porosity” or “specific pore volume”(used interchangeably to mean the same thing) of a material is thevolume of the material per unit of mass that corresponds to pores,channels, and other voids in the material structure. A material'sspecific porosity can be determined using the BET method and/orBarrett-Joyner-Halenda (BJH) pore volume analysis.

As used herein, the term “reacting” refers to the bringing together ofchemical reagents in such a manner to allow their interaction at themolecular level to achieve a chemical or physical transformation.Reacting can involve two reagents, where one or more equivalents ofsecond reagent are used with respect to the first reagent. Reacting canalso involve more than two reagents.

In this disclosure, materials such as calcium carbonate, calcium oxide,and calcium phosphate compositions are referenced in various preparativesteps as being heated to a specific temperature or to a temperaturewithin a specific range. In general, heating a material to a particulartemperature involves setting an internal temperature of an oven,furnace, or other heating device to the particular temperature. Thematerial that is heated within the oven, furnace, or other heatingdevice may be heated uniformly (i.e., through the entire thickness ofthe material) to the particular temperature, or a thermal gradient mayexist within the material such that, for example, at least a portion ofan outer surface of the material is heated to within ±10% of theparticular temperature, while interior regions of the material may beheated to temperatures less than the particular temperature. It shouldbe understood that for purposes of this disclosure, heating a materialto a particular temperature means that at least a portion of thematerial (i.e., at least a region of an outer surface of the material)is heated to within ±10% of the particular temperature, but does notnecessarily mean that the entire material is heated to the specifiedtemperature, nor that the entire material is heated to a uniform,gradient-free temperature.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the subject matter herein, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

The details of one or more embodiments are set forth in the accompanyingdrawings and the description below. Other features and advantages willbe apparent from the description, drawings, and claims.

DESCRIPTION OF DRAWINGS

FIG. 1 is a schematic diagram of a series of steps for producing calciumphosphate compositions.

FIG. 2 is a plot showing volume of HCl solution neutralized as afunction of time for a calcium hydroxide solution produced from reactivecalcium oxide.

FIG. 3 is a plot showing pH as a function of H₃PO₄ concentration in anintermediate solution used to produce calcium phosphate compositions.

FIG. 4 is a plot showing scattered x-ray intensity as a function ofangle for a calcium phosphate composition.

FIGS. 5A and 5B are scanning electron microscope images of a sample ofamorphous calcium phosphate at two different magnifications.

FIG. 6 is a scanning electron microscope image of a triphasic calciumphosphate composition.

FIGS. 7A and 7B are scanning electron microscope images of a biphasiccalcium phosphate composition at two different magnifications.

FIGS. 8A-8C are scanning electron microscope images of a calciumphosphate composition at different magnifications.

FIGS. 9A and 9B are scanning electron microscope images of anothercalcium phosphate composition at different magnifications.

FIGS. 10A and 10B are scanning electron microscope images of a furthercalcium phosphate composition at different magnifications.

FIG. 11 is a scanning electron microscope image of another calciumphosphate composition.

FIG. 12 is a scanning electron microscope image of a further calciumphosphate composition.

FIG. 13 is a plot showing x-ray scattering intensity as a function ofangle for a calcium phosphate composition.

FIG. 14 is a plot showing infrared transmittance as a function ofwavenumber (i.e., an infrared absorption spectrum) for the compositionof FIG. 13.

Like reference symbols in the various drawings indicate like elements.

DETAILED DESCRIPTION I. Introduction

Calcium phosphates are widely used industrial compounds. In particular,monophasic calcium phosphates such as hydroxyapatite find application indental and medical products, fertilizer production, food production andproducts, and industrial chemical production. However, the economic andenvironmental costs associated with producing monophasic chemicalphosphate compounds have limited the uses of these compounds.

Biphasic and triphasic chemical phosphate compositions promise evengreater utility, as the properties of such compositions can conceivablybe tailored even more specifically for advantageous use in variousapplications. However, at present, industrial-scale methods forreproducible production of biphasic and triphasic chemical phosphatecompositions with well controlled chemical and physical properties donot exist. This absence of viable large scale production routes leavesthe promise of such compositions unfulfilled.

The present disclosure describes methods for controlled, reproducible,large scale production of chemical phosphate compositions. By adjustingthe reagents and conditions involved, the chemical and physicalproperties of the compositions can be controlled in a systematic manner.This allows desired products to be prepared in large volumes on demand,at a cost that is significantly lower than conventional productionmethods. Moreover, the methods disclosed herein permit certain productsfor which no other large-scale production route exists—such as biphasicand triphasic calcium phosphate compositions within certaincompositional ranges—to be produced.

In the following sections, a general overview of the productions methodsis first discussed, followed by a discussion of individual stages of themethods. This disclosure also provides a large number of examplesdemonstrating controlled, on-demand fabrication of a wide variety ofdifferent calcium phosphate compositions with various combinations ofchemical and physical properties.

II. General Overview

The methods disclosed herein produce calcium phosphate compositions in atwo-stage reaction with aqueous calcium hydroxide solution. In turn, theaqueous calcium hydroxide solutions are prepared by dissolving areactive calcium oxide product in water. Due to their reactivity,calcium oxides provide a synthetic route to calcium phosphates that issignificantly less expensive than existing synthetic schemes atindustrial-scale production volumes. In addition, the methods disclosedherein yield much larger quantities of calcium phosphate compositions,relative to conventional synthetic methods, in equivalent time periods.

The general methodology for the synthesis of calcium phosphatecompositions is as follows. First, a reactive calcium oxide (CaO)precursor material is added to water to form a calcium hydroxidesolution:

reactive CaO+H₂O→Ca(OH)₂  [1]

Then, a portion of the calcium hydroxide solution is combined withphosphoric acid to yield an intermediate calcium dihydrogen phosphateproduct in a solution or slurry:

Ca(OH)₂+H₃PO₄→Ca(H₂PO₄)₂  [2]

Finally, the calcium dihydrogen phosphate intermediate product iscombined with another calcium hydroxide solution, prepared in the samemanner as shown in Equation (1), to yield a calcium phosphate product:

Ca(H₂PO₄)₂+Ca(OH)₂→Ca₃(PO₄)₂  [3]

In Equation (3), the calcium phosphate product is shown with the nominalchemical formula Ca₃(PO₄)₂ for illustrative purposes. However, it shouldbe understood that, depending upon the reaction conditions in Equations(1)-(3), the calcium phosphate compositions produced can includephosphate ions (i.e., orthophosphate ions), metaphosphate ions, and/orpyrophosphate ions, including mixtures of these anionic species. Byadjusting the reaction conditions, control over the composition,structure, and physical properties of the calcium phosphate compositionsproduced can be achieved.

Further, it should be understood that while the methods discussed hereinrefer to Ca(OH)₂ solutions produced from a common reactive CaOprecursor, Ca(OH)₂ solutions produced from different CaO precursormaterials—including non-reactive CaO precursor materials—can also beused. The use of a reactive CaO precursor material ensures high yieldsand conversion rates, and reduced production times due to fastdissolution of the reactive CaO in water. However, CaO materials derivedfrom production processes other than those disclosed herein (i.e.,processes that do not yield reactive CaO) can also be used to prepareCa(OH)₂ solutions that can be used to prepare calcium phosphatecompositions according to Equations (2) and (3), and using the methodsdisclosed herein. Production of calcium phosphate compositions startingwith non-reactive calcium oxide materials is therefore within the scopeof this disclosure.

FIG. 1 is a flow chart 100 showing a series of general steps for thepreparation of a variety of different calcium phosphate compositions. Ina first step 102, reactive CaO is prepared from a precursor calciumcarbonate (CaCO₃) material by heat treatment of the CaCO₃ particles. Instep 104, a first quantity of the reactive CaO is dissolved in water toform an aqueous Ca(OH)₂ solution, which is then combined with aphosphate source such as phosphoric acid (H₃PO₄) in step 106 to form aslurry of aqueous Ca(H₂PO₄)₂. Then, in step 108, a second quantity ofthe reactive CaO is dissolved in water to form a second aqueous Ca(OH)₂solution, which reacts with the aqueous Ca(H₂PO₄)₂ to form the calciumphosphate compositions. The process terminates at step 112.

Subsequent sections of this disclosure discuss the steps shown in FIG. 1is greater detail, and the chemical and physical properties of calciumphosphate compositions prepared according to the procedure shown in FIG.1.

III. Preparation of Reactive Calcium Oxide

The first step 102 of flow chart 100 includes the production of reactivecalcium oxide from a calcium carbonate precursor material. In general,the production method involves the thermal decomposition of calciumcarbonate to yield CaO and CO₂, as shown in Equation (1). Naturalsources of calcium carbonate include materials such as limestone andseashells. In principle, calcium carbonate derived from any source canbe thermally decomposed to yield reactive CaO. However, to ensure thatthe reactive CaO produced is low in impurities and has a relativelyuniform size distribution, and to ensure high conversion rates withrelatively low volume of byproducts produced, high quality limestone istypically used as the source of CaCO₃.

For a particle of limestone that is converted to CaO by thermaldecomposition, the decomposition process begins on the surface of theparticle and proceeds inwards toward the center of the particle as moreheat is absorbed. At room temperature, solid limestone (CaCO₃) particlesare stable. Upon heating to a suitable temperature, CO₂ is eliminated,leaving behind solid CaO particles. Because heating establishes athermal gradient within the particle, at a particular time following thestart of thermal decomposition, the particle will contain a limestonecore surrounded by a calcined layer of CaO. The active eliminationreaction occurs in the reaction zone, on the narrow border between thetwo regions.

Two processes occur during the reaction. Heat transfer to the CaCO₃ tothe surface of the CaCO₃ particle occurs to raise the temperature of theCaCO₃ to initiate CO₂ dissociation. In the zone where dissociation ofCO₂ is occurring, the temperature is approximately constant. As thereaction zone migrates deeper into the particle, subsequent quantitiesof heat penetrate the already-converted portions of the CaCO₃ particle(which now consist of CaO) to reach the reaction zone and maintain theelimination reaction.

Mass transfer also occurs within the CaCO₃ particle. CO₂ gas produced inthe reaction zone diffuses from the interior of the particle to theexterior surface of the particle, through the newly formed CaO layer.

The temperature at which CaCO₃ dissociates to form CaO depends on theCO₂ pressure/concentration in the CaO layer in contact with the reactionzone. Because the reaction shown in Equation (1) is an equilibriumreaction, a large concentration or partial pressure of CO₂ in contactwith the reaction zone will tend to favor the reactant (i.e., CaCO₃) inEquation (1), limiting the conversion rate and yield of CaO. Incontrast, the lower the concentration/pressure of CO₂ in the CaO layer,the greater the extent to which the products (i.e., CaO) are favored inEquation (1). In turn, the greater the extent to which CaO is favored inEquation (1), the lower the temperature required to drive conversion ofCaCO₃ into CaO.

In a typical limestone calcination furnace, the total gas pressure isapproximately 1 atm, and CO₂ represents about 30% of the gas volumewithin the furnace. At this CO₂ concentration, the CaCO₃ at the exteriorsurface of a limestone particle will dissociate at a temperature ofabout 830° C.

In the interior of the particle, CO₂ dissociation from the reaction zonethrough the CaO layer to the exterior particle surface occurs only whenthe CO₂ pressure in the reaction zone exceeds the CO₂ partial pressureexterior to the particle in the furnace. By reducing CO₂pressure/concentration within the furnace, the yield of CaO fromEquation (1) can be increased and/or the temperature at which thereaction can be performed decreases. As mentioned above, where thepartial pressure of CO₂ in the furnace is approximately 0.33 atm, CaCO₃dissociation occurs at temperatures of approximately 830° C. and higher.When the partial pressure of CO₂ in the furnace is approximately 1 atm,CaCO₃ dissociation occurs at temperatures of approximately 902° C. andhigher.

To initiate and maintain the reaction in Equation (1), heat istransmitted from the exterior of the particle to the interior throughthe enclosing CaO layer, which grows in thickness over time. Forefficient heat transfer, a temperature gradient should exist between theexterior surface of the particle and the reaction zone. The magnitude ofthe gradient for efficient conversion to CaO depends on the particlesize once the initial CaO layer is formed because CaO is a relativelypoor heat conductor. In general, the larger the temperature differencebetween the exterior surface of the particle and the reaction zone, thefaster the propagation of heat to the reaction zone.

However, when the surface CaO layer is heated, contraction ofcapillaries in the layer occurs as a by-product of crystal growth andre-growth, and crystal coalescence. Reduction of the porosity of the CaOlayer hinders the diffusion of CO₂ out of the particle from theever-deeper reaction zone. As CO₂ is prevented from diffusing out of theinterior region of the particle, the partial pressure/concentration ofCO₂ in the region of the particle adjacent to the reaction zoneincreases, which favors the reactant CaCO₃ in Equation (1), as discussedabove. Thus, as CO₂ diffusion out of the interior of the particle ishindered, the temperature in the reaction zone may need to be increasedto maintain conversion of CaCO₃ to CaO.

At very high temperatures (e.g., 1300-1400° C.), the surface CaO onparticles undergoing thermal decomposition can sinter, leading to asignificant reduction in the number and sizes of pores within the CaOlayer. In turn, it becomes much more difficult for CO₂ generated in thereaction zone to diffuse through the CaO layer and out of the particle,which slows (or even stops) the rate of conversion of CaCO₃ to CaO.Sintering is a challenging problem to overcome when using limestone fromsources with a wide variation in particle sizes. For example, when adistribution of CaCO₃ particles with sizes from 30 mm to 120 mm is used,to convert all of the CaCO₃ in the largest of the particles to CaO,temperatures of 1300-1400° C. are appropriate. At these temperatures,however, many of the smaller particles will sinter preventing completeconversion of these particles to CaO. Alternatively, at lowertemperatures, sintering of the smaller CaCO₃ can be avoided, resultingin higher CaO conversion rates for these particles. But at lowertemperatures, not all of the CaCO₃ in the larger particles is convertedto CaO, as the thermal gradient in the particle interiors is notsufficient to drive the reaction in Equation (1) as the reaction zonemigrates further toward the centers of the particles.

The loss of pore volume in both large and small CaCO₃ at hightemperatures can also negative affect the reactivity of the CaOparticles that are produced. CaO reactivity with a variety of reagents(including water) is strongly influenced by the presence of pores. Ingeneral, the larger the number and diameter of the pores in the CaOparticles that are produced, the larger the surface area of theparticles. Because chemical reactions occur on the surfaces ofparticles, the rates of many reactions depend on the effective surfacearea of the particles on which they occur. Particles with larger surfaceareas typically undergo faster reactions, all other conditions beingequal, because the reactions occur at a larger number of sites per unittime.

Thus, when CaCO₃ particles are heated to temperatures that significantlyreduce the pore volume, not only is it possible that the reduction inpore volume will attenuate the conversion of CaCO₃ to CaO, it is alsopossible that the reduction in pore volume will render the resulting CaOparticles less reactive in subsequent processes such as dissolution inwater.

Certain types of impurities that may be present in naturally-derivedCaCO₃ particles (such as limestone particles, for example) may alsobecome more troublesome at higher processing temperatures. For example,the reaction between certain impurities and CaO increases at highertemperatures. Thus, a certain percentage of the CaO product can berendered unavailable due to reaction and formation of by-products withnaturally occurring impurities in the reactant material. This reducesthe overall conversion rate and results in a less “reactive” CaOproduct.

The foregoing considerations imply that to ensure a high conversion ratefrom CaCO₃ to CaO, and to produce a reactive CaO product, both theproperties of the starting material (CaCO₃ particles) and the reactionconditions should be carefully controlled. In other words, it is thecombination of these factors that produces a highly reactive product ata nearly 100% conversion rate.

With regard to particle size control, raw limestone chunks having a widerange of sizes are typically obtained and impact crushed to producesmaller particles. The smaller particles are then separated into a rangeof sizes using sequential sieves. This sorting process yieldsdistributions of particles having a relatively narrow range of sizes. Ingeneral, the number of particle distributions depends on the number andconfiguration of sieves used to sort the particles after impactcrushing. In some embodiments, for example, three differentdistributions of particles are obtained, each corresponding to adifferent mean particle size.

The distribution of particles that is processed via thermaldecomposition typically has a carefully selected range of particlesizes. As discussed above, the particle sizes play an important role inthe success of the conversion process. Particles that are too large maynot be fully converted to CaO, leading to an impure product that stillincludes appreciate quantities of CaCO₃. Particles that are too smallmay also not be fully converted to CaO, as sintering may preventefficient diffusion of CO₂ out of the interior of the particles. Inaddition, sintering may yield a CaO product with lower-than-expectedreactivity on account of the reduction in pore volume that is aby-product of sintering.

In some embodiments, the mean size of the CaCO₃ particles used toproduce CaO is about 6 mm. For a distribution of particles with a meansize of about 6 mm, the full width at half maximum (FWHM) of theparticle size distribution is about 4 mm or less (e.g., about 3 mm orless, about 2 mm or less, about 1 mm or less). In certain embodiments,the mean size of the CaCO₃ particles used to produce CaO is about 10 mm.For a distribution of particles with a mean size of about 10 mm, thefull width at half maximum (FWHM) of the particle size distribution isabout 4 mm or less (e.g., about 3 mm or less, about 2 mm or less, about1 mm or less). In some embodiments, the mean size of the CaCO₃ particlesused to produce CaO is about 14 mm. For a distribution of particles witha mean size of about 14 mm, the full width at half maximum (FWHM) of theparticle size distribution is about 4 mm or less (e.g., about 3 mm orless, about 2 mm or less, about 1 mm or less).

In some embodiments, the CaCO₃ particles used to produce CaO have adistribution of sizes between 4 mm and 8 mm. In certain embodiments, theparticles have a distribution of sizes between 8 mm and 12 mm. In someembodiments, the particles have a distribution of sizes between 12 mmand 16 mm.

Another important consideration is the presence of impurities in theCaCO₃ reactant particles. As explained above, certain impurities in theCaCO₃ can react with the CaO product, forming products in which CaO isbound and no longer available for subsequent reactions. As one example,certain limestones have relatively high quartz (i.e., SiO₂)concentrations. Quartz reacts with CaO, yielding calcium silicateproducts, 2CaO.SiO₂. In other words, each SiO₂ molecule reacts with twoCaO molecules, yielding a relatively inert silicate product in which CaOis no longer available to react with most reagents, including water.

To avoid producing low reactivity CaO products in this manner, it hasbeen found in general that the CaCO₃ particles used in Equation (1) toproduce reactive CaO should have a chemical composition in which theconcentration of CaCO₃ is at least 94%. To produce even higherreactivity CaO products, the concentration of CaCO₃ in the reagentparticles is 95% or more (e.g., 97% or more, 98% or more, 99% or more,99.5% or more, 99.9% or more).

To produce CaO particles from CaCO₃ particles, the CaCO₃ particles areheated to a relatively high temperature in a furnace. A variety ofdifferent furnaces can be used for this purpose, including but notlimited to a horizontal rotary furnace, a vertical furnace, a naturaldraft furnace, a forced air furnace, a forced draft furnace, acondensing furnace, a one-stage or multi-stage furnace, a modulatingfurnace, a blast furnace, a puddling furnace, a reverberatory furnace,an open hearth furnace, and an induction furnace. The furnace caninclude one or more temperature measurement devices for measuring theinternal furnace temperature during the conversion process. Examples ofsuch devices include, but are not limited to, thermistors,thermocouples, resistance thermometers, and silicon bandgap temperaturesensors.

To efficiently convert CaCO₃ particles to CaO particles, the CaCO₃particles are heated to a relatively high temperature. In general, evenheating of the CaCO₃ particles is important to avoid sintering andachieve a high conversion rate. As discussed above, heating the CaCO₃particles to a temperature equal to or greater than a minimumtemperature initiates the thermal decomposition of CaCO₃. In someembodiments, for example, the CaCO₃ particles are heated to atemperature greater than 900° C. (e.g., greater than 950° C., greaterthan 1000° C., greater than 1050° C., greater than 1100° C., greaterthan 1150° C.) to initiate thermal decomposition. In certainembodiments, the temperature is between 1000° C. and 1200° C. (e.g.,between 1050° C. and 1200° C., between 1100° C. and 1200° C., between1150° C. and 1200° C.).

To ensure that the porosity of the CaO particles is not reducedsubstantially, the temperature of the CaCO₃ particles can be maintainedbelow a maximum temperature. For example, in certain embodiments, thetemperature of the CaCO₃ particles throughout the thermal decompositionprocess is maintained below a temperature of 1200° C. (e.g., below 1150°C., below 1100° C., below 1050° C., below 1000° C.).

During thermal decomposition of the CaCO₃ particles, the temperature ofthe particles can be maintained between 900° C. and 1200° C. (e.g.,between 950° C. and 1200° C., between 900° C. and 1150° C., between 950°C. and 1150° C., between 1000° C. and 1150° C., between 1000° C. and1100° C., at about 1150° C.). By heating the CaCO₃ particles totemperatures at which thermal decomposition occurs and, at the sametime, significant reductions in porosity are avoided, conversion of theparticles to form reactive CaO particles occurs relatively rapidly. Insome embodiments, for example, the CaCO₃ particles are heated for aperiod of 3.0 hours or less (e.g., 2.75 hours or less, 2.50 hours orless, 2.25 hours or less, 2.0 hours or less, 1.75 hours or less, 1.5hours or less, 1.25 hours or less, 1.0 hours or less) to form the CaOparticles. In certain embodiments, the CaCO₃ particles are heated for aperiod of at least 1.0 hour (e.g., at least 1.5 hours, at least 2.0hours, at least 2.5 hours) to form the CaO particles. In someembodiments, the CaCO₃ particles are heated for a period of between 1.0hour and 3.0 hours (e.g., between 1.5 hours and 3.0 hours, between 2.0hours and 3.0 hours).

In some embodiments, the CaCO₃ particles are heated to a constanttemperature to effect the conversion to CaO particles. However, asdiscussed above, as the CaO “shell” forms on the particles and thereaction zone migrates inward towards the particle centers, a largerthermal gradient may be needed to ensure that the temperature in thereaction zone reaches the minimum temperature for the decompositionreaction. Accordingly, in certain embodiments, heating occurs in two ormore stages, where the temperature at each stage is higher than at theimmediately preceding stage, and each stage occurs for a portion of thetotal heating period. For example, in a two-stage heating process, theCaCO₃ particles are first heated to a temperature in a range 900-1150°C. for a period of 5 mins. to 1 hour, and then heated to a temperaturein a range 1150-1200° C. for a period of 5 mins. to 1 hour. As anotherexample, in a three-stage heating process, the CaCO₃ particles are firstheating to a temperature of between 900° C. and 1000° C., then heatingto a temperature of between 1000° C. and 1100° C., and then to atemperature of between 1100° C. and 1200° C. Each stage can be performedfor a period of between 5 mins. to 2 hours.

In general, multi-stage heating processes involving any number of steps,any temperature range from 900° C. to 1200° C. for each of the steps,and any time period between 5 minutes and three hours for each of thesteps can be implemented. By using a multi-stage heating process, thethermal gradient within the CaCO₃ particles can be adjusted as thereaction zone migrates within the particles, which can allow a higherconversion rate and can shorten the overall conversion time.

In some embodiments, the heating process can be implemented as acontinuous temperature increase from a lower temperature limit to anupper temperature limit. In general, lower and upper temperature limitsfrom 900° C. to 1200° C. can be used for this purpose. For example, thetemperature can be increased linearly between a first temperature in therange 900-1000° C., and a second temperature in the range 1100-1200° C.,within the heating period.

Similar to step-wise increases in temperature, a continuous temperatureincrease can be used to match the temperature gradient within the CaCO₃particles to the migration of the reaction zone. The temperature canvary (i.e., increase) linearly in some embodiments. However, a nonlineartemperature variation can also be used. In particular, for example,where the migration of the reaction zone is expected to occurnonlinearly in time through the CaCO₃ particles, the temperature canalso increase nonlinearly in time.

In the foregoing methods, temperatures are established and maintainedwithin the furnace based on measurements from the temperaturemeasurement device. Such measurements allow particular temperatures tobe achieved, and for the monitoring of temperatures within the furnaceduring the thermal decomposition process. The temperature measurementscan be used as feedback signals to control furnace heating at any stageof the process.

Using the methods disclosed above, reactive CaO is produced from CaCO₃.A “reactive” CaO is one that reacts rapidly with water, leading tofaster dissolution. Faster dissolution is important for production ofcalcium phosphate compositions on an industrial scale, as the aqueousCa(OH)₂ solution that is produced is a key reagent in the production ofthe compositions.

The reactivity of the CaO produced as discussed above with water is aproduct of the CaO's surface area, porosity, particle size, and purity.The methods discussed above are designed to yield CaO products withfavorable attributes in each respect, ensuring that they will be highlyreactive. For example, using the methods disclosed above, the surfacearea of the CaO particles is at least 6.0 m²/g (e.g., at least 8.0 m²/g,at least 10.0 m²/g, at least 12.0 m²/g, at least 14.0 m²/g, at least20.0 m²/g).

The methods also yield CaO particles with relatively high porosity. Forexample, CaO particles produced as discussed above have specificporosity of at least 15.0 cm³/g (e.g., at least 20.0 cm³/g, at least25.0 cm³/g, at least 30.0 cm³/g, at least 35.0 cm³/g, at least 40.0cm³/g, at least 50.0 cm³/g).

CaO particles produced as discussed above have a relatively narrowdistribution of sizes that matches the distribution of CaCO₃ particlesizes used to produce the CaO particles. In some embodiments, forexample, the distribution of CaO particles has a mean particle size of 6mm, and a FWHM of 4 mm or less (e.g., 3 mm or less, 2 mm or less, 1 mmor less). In certain embodiments, the distribution of CaO particles hasa mean particle size of 10 mm, and a FWHM of 4 mm or less (e.g., 3 mm orless, 2 mm or less, 1 mm or less). In some embodiments, the distributionof CaO particles has a mean particle size of 14 mm, and a FWHM of 4 mmor less (e.g., 3 mm or less, 2 mm or less, 1 mm or less).

In some embodiments, the CaO particles that are produced have adistribution of sizes between 4 mm and 8 mm. In certain embodiments, theparticles have a distribution of sizes between 8 mm and 12 mm. In someembodiments, the particles have a distribution of sizes between 12 mmand 16 mm.

By starting with relatively pure CaCO₃ particles and heating theparticles to relatively high temperatures (which thermalizes certainimpurities that may be present), high purity CaO particles can beproduced. In some embodiments, for example, the CaO concentration in CaOparticles produced as disclosed herein is 97% or more (e.g., 98% ormore, 99% or more, 99.5% or more, 99.9% or more).

The concentration of residual CaCO₃ in the CaO is typically very low.For example, in some embodiments, the concentration of CaCO₃ in the CaOparticles after heating as discussed above is 0.5% or less (e.g., 0.3%or less, 0.1% or less, 0.05% or less, 0.01% or less, 0.005% or less,0.001% or less).

The overall efficiency of the conversion process is generally very high.The efficiency is defined as the percentage of CaCO₃ in the CaCO₃particles that is converted to CaO in the product particles. Typically,the efficiency of conversion is 95% or greater (e.g., 97% or greater,99% or greater, 99.5% or greater, 99.9% or greater, 99.99% or greater).

The reactivity of calcium oxide can be determined using the Withermethod. The Wither method measures the ability of calcium oxide toundergo hydration. The reactivity of a CaO sample is determined byprogressive reaction with water (to form calcium hydroxide) andneutralization of the resulting basic solution with 4N hydrochloricacid. Because the reaction with water takes place at the interfacebetween the solid CaO particles and the aqueous solution, the specificsurface area of the CaO particles has a significant effect on thereactivity index that is determined.

During the test, the alkaline Ca(OH)₂ that is formed upon reaction ofCaO with water is neutralized with the hydrochloric acid, and the volumeof hydrochloric acid used is recorded. The time elapsed since theinitiation of the reaction is also recorded. More reactive CaO samplesrequire a larger volume of hydrochloric acid for neutralization atearlier times, indicating that they react more rapidly with water.

FIG. 2 is a graph showing Wither test results for 50 g of a reactivecalcium oxide material produced as disclosed herein (curve 202), and for50 g samples of two commercially available calcium oxide materials(curves 204 and 206). As shown in the graph, the reactivity of thereactive calcium oxide material was significantly higher than thereactivities of the commercially available calcium oxide materials. Themaximum theoretical volume of 4N hydrochloric acid required toneutralize 50 g of pure CaO is about 446 mL. The reactive CaO shown incurve 202 required 418 mL, very close to the theoretical value.

IV. Production of Calcium Phosphate Compositions

Returning to FIG. 1, the next step 104 includes preparing an aqueousCa(OH)₂ solution by dissolving the reactive CaO particles from step 102in water. It should be noted that step 108 also involves the preparationof an aqueous Ca(OH)₂ solution from the reactive CaO particles preparedin step 102. The two Ca(OH)₂ solutions are typically prepared at thesame time, with suitable quantities of reactive CaO dissolved in waterto prepare each solution. Dissolving the reactive CaO particles in wateryields a homogeneous solution at alkaline pH of fully solvated calciumions. For this reason, while using reactive CaO to prepare the solutionshas certain advantages in terms of faster production times, it shouldalso be noted that Ca(OH)₂ solutions prepared from other CaO particlescan also be used the preparation of calcium phosphate compositions asdisclosed herein.

The concentrations of calcium ions (Ca²⁺) in the two solutions can bethe same or different. Where the concentrations differ, depending uponthe nature of the calcium phosphate composition to be produced, thecalcium ion concentration in the first Ca(OH)₂ solution can be greaterthan or less than the calcium ion concentration in the second Ca(OH)₂solution.

In some embodiments, the concentration of calcium ions in the firstsolution is 1.0 mol/L or more (e.g., 1.25 mol/L or more, 1.5 mol/L ormore, 1.75 mol/L or more, 2.0 mol/L or more, 2.5 mol/L or more, 3.0mol/L or more). In certain embodiments, the concentration of calciumions in the second solution is 1.0 mol/L or more (e.g., 1.25 mol/L ormore, 1.5 mol/L or more, 1.75 mol/L or more, 2.0 mol/L or more, 2.5mol/L or more, 3.0 mol/L or more).

Next, in step 106, an aqueous solution of phosphoric acid (H₃PO₄) isadded to the first Ca(OH)₂ solution to eventually generate an aqueousslurry of Ca(H₂PO₄)₂. The generation of this compound as a stableintermediate species in solution is a key step in the overall syntheticmethod, as the Ca(H₂PO₄)₂ intermediate species acts as a common“baseline” compound from which a wide variety of final calcium phosphatecompositions can be generated.

To generate the Ca(H₂PO₄)₂ intermediate product, the H₃PO₄ solution isadded slowly with stirring to the first Ca(OH)₂ solution. Stirring canbe implemented, for example, using two counter-rotating blades in thesolution). It is important that the H₃PO₄ solution is not added tooquickly, or amorphous Ca₃(PO₄)₂ will precipitate from solution. Onceprecipitated in this relatively inert form, the calcium and phosphateions are no longer available to further steps in the synthetic method.In some embodiments, the concentration of phosphoric acid in the H₃PO₄solution is 4.0 mol/L or more (e.g., 4.5 mol/L or more, 5.0 mol/L ormore, 5.25 mol/L or more, 5.50 mol/L or more, 5.75 mol/L or more).

The requirement that the H₃PO₄ solution be added slowly arises from themulti-valent nature of the phosphate ion. In aqueous solution atdifferent pH values, the phosphate ion can variously exist in its fullydeprotonated form PO₄ ³⁻, in its doubly deprotonated form HPO₄ ²⁻, andin its singly deprotonated form H₂PO₄ ⁻. When the pH of the solutionchanges slowly in a controlled fashion, each of these anionic forms ofthe phosphate ion can be generated. However, when the pH of the solutionchanges rapidly and counterions of a relatively insoluble phosphate saltare present in solution as a result of the pH change, precipitation ofthe salt tends to occur.

In effect, the various forms of the phosphate anion form a multi-stagebuffer solution when pH changes are not too rapid. But when a largequantity of acid, for example, is added to the solution, the bufferednature of the solution is overcome and precipitation of a salt—wherepossible—tends to occur.

Slow addition of the H₃PO₄ solution with stirring ensures that the pH ofthe Ca(OH)₂ solution changes slowly, and that insoluble phosphate saltsdo not precipitate from solution. As the pH of the solution is slowlylowered, each of the intermediate phosphate ion species can be generatedin a solution that is naturally buffered, until the intermediatedihydrogen phosphate product, Ca(H₂PO₄)₂, is generated as a slurry.

The manner in which the pH of the combined Ca(OH)₂ and H₃PO₄ solutionschanges in shown schematically in the graph of FIG. 3. Initially, thefirst Ca(OH)₂ solution has a pH of about 12. The H₃PO₄ solution is addedsuch that the pH of the combined solution is reduced in a series ofstages. In the first stage, addition of the H₃PO₄ solution continuesslowly, with stirring, until the solution pH reaches a value of between8.5 and 9.5, as shown by the plateau region 302 in FIG. 3. The solutionpH stabilizes at this value and is maintained by buffering between PO₄³⁻ and HPO₄ ²⁻ ions.

After the first stage pH has been reached and the solution pH hasstabilized for at least 1 minute, addition of the H₃PO₄ solutionrecommences slowly with stirring in the second stage, until the solutionpH reaches a value of between 3.5 and 4.5, represented by the plateauregion 304 in FIG. 3. At this pH value, the solution pH stabilizes andis maintained by buffering between HPO₄ ²⁻ and H₂PO₄ ⁻ ions.

After the second stage pH has been reached and has stabilized for atleast 1 minute, additional H₃PO₄ solution is added to the combinedsolution slowly, with stirring, until the pH of the combined solutionreaches a value of between 1 and 2 (and in particular, between 1.4 and1.7), represented by the plateau region 306 in FIG. 3. At this pH value,conversion of phosphate ions to H₂PO₄ ⁻ ions has been optimized (or isapproximately optimum), and the salt Ca(H₂PO₄)₂ precipitates weakly fromsolution, as it is mildly insoluble.

If stabilization of the solution pH at each of the three stages 302,304, and 306 does not occur, for example because the H₃PO₄ solution wasadded too rapidly, then inert and amorphous Ca₃(PO₄)₂ will precipitatefrom solution as discussed above, which significantly reduces theoverall yield of calcium phosphate compositions of interest that areproduced. That is, when aqueous H₃PO₄ is added too quickly such that alarge excess concentration of PO₄ ³⁻ is instantaneously present in thesolution, the result is rapid precipitation of relatively insolublesolid Ca₃(PO₄)₂.

In certain embodiments, to adjust the rate at which the pH of thesolution changes as H₃PO₄ is added, the temperature of the H₃PO₄solution can be controlled. For example, the temperature of the H₃PO₄solution is between 0° C. and 40° C. (e.g., between 5° C. and 15° C.,between 5° C. and 30° C., between 10° C. and 40° C., between 15° C. and25° C., between 15° C. and 40° C., between 20° C. and 40° C., between25° C. and 40° C., between 30° C. and 40° C.).

Next, in step 108, a calcium phosphate composition is prepared from thein situ Ca(H₂PO₄)₂ intermediate product. To prepare the calciumphosphate composition, the second Ca(OH)₂ solution is added slowly, withstirring, to the Ca(H₂PO₄)₂ slurry. Addition of the second Ca(OH)₂solution increases the pH of the Ca(H₂PO₄)₂ slurry. As discussed above,the concentration of calcium ions in the second Ca(OH)₂ solution differsfrom the concentration of calcium ions in the first Ca(OH)₂ solution.The relative molar ratios of calcium and phosphate ions as well as thepH of the combined Ca(H₂PO₄)₂ slurry and second Ca(OH)₂ solutionscontrols the stoichiometry of the calcium phosphate composition that isproduced, and also influences the physical properties of thecomposition.

In general, the molar ratio of calcium ions to dihydrogen phosphate ionsin the slurry influences the number of phases and the chemicalcomposition of the phases in the product calcium phosphate composition.In some embodiments, the molar ratio of the calcium dihydrogen phosphateions to the calcium hydroxide ions is from about 0.25:1 to about 4:1(e.g., from about 0.4:1 to about 1.17:1, from about 0.5:1 to about1.1:1, about 1:1.7, about 1:1).

The final pH of the product solution, after all of the second Ca(OH)₂solution has been added, depends upon the concentration and volume ofthe second Ca(OH)₂ solution. In some embodiments, the final pH isbetween 6.0 and 8.0 (e.g., between 6.5 and 7.5, about 7.0). In certainembodiments, the final pH is between 9.0 and 13.0 (e.g., between 10.0and 13.0, between 11.0 and 13.0, between 11.5 and 12.5, about 12.0).

Addition of the second Ca(OH)₂ solution to the thick Ca(H₂PO₄)₂ slurrytypically occurs slowly to avoid formation of a semi-solid mass. Thefinal product calcium phosphate composition is obtained as an aqueousslurry, in a water:product ratio of about 12:1. In step 110, after theproduct calcium phosphate composition has been formed as a slurry, theslurry is isolated and purified. To isolate the product composition, theslurry can be heated in a rotary furnace to drive off of some of thewater, yielding a reduced mixture with a water:product ratio of about4:1. The reduced mixture can then be heated in a second furnace to driveoff the remaining water, yielding the calcium phosphate composition insolid form. This two-stage isolation and purification process istypically used to avoid generating a solid calcium phosphate compositionin the form of a hard block, which is difficult to process mechanically.Process water evaporated during both drying phases can be recovered andre-used upstream in the synthetic method to generate additionalquantities of the first and second Ca(OH)₂ solutions.

To yield calcium phosphate products with desired particle sizes, thesolid calcium phosphate composition can be mechanically ground intoparticles with a desired size distribution. Further treatment in amicronizer can be used to produce very small particles for use inspecific applications. Calcium phosphate compositions with bimodal andother multimodal distributions of particle sizes can be produced bygrinding and sieving different batches of the same product calciumphosphate composition to yield particles of different mean size and sizedistributions, and then combining the batches of to yield a calciumphosphate composition with a bimodal or other multimodal particle sizedistribution.

Even smaller particles (e.g., micrometer- and/or nanometer-sizedparticles) can be generated by subjecting the product to a thermal shocktreatment. The thermal shock treatment can also be used to introduceand/or augment the distribution and sizes of pores in the productcalcium phosphate composition. In this procedure, the temperature of theproduct composition is rapidly increased during the second stage ofisolation and purification discussed above. As the temperature risesabove the boiling point of the water trapped in the otherwise solidproduct composition, the water is converted to steam. As the steamescapes from the particles of the product composition, the internalstructure of the particles is disrupted, creating pores and channels inthe particles.

The thermal shock treatment can be performed as follows. An oven isheated to a temperature of about 500° C., and portions of theproduct—which are at temperatures of between 20-30° C. —are introducedslowly, so that the temperature within the oven remains above about 450°C. Each portion of the product is heated for about 15 minutes in theoven at 450-500° C. to effect thermal shock.

The increase in porosity of the product composition that results fromthermal shock treatment depends significantly on the temperature towhich particles of the product composition are heated. In someembodiments, product particles are heated to a temperature of 200° C. ormore (e.g., 300° C. or more, 400° C. or more, 500° C. or more, 600° C.or more, 700° C. or more, 800° C. or more, 900° C. or more). Theincrease in temperature of the product particles during thermal shocktreatment is typically at least 400° C. (e.g., at least 450° C., atleast 500° C., at least 550° C., at least 600° C., at least 700° C.).The particles are typically heated for a duration of between 5 minutesand 30 minutes (e.g., between 5 minutes and 20 minutes, between 10minutes and 30 minutes, between 10 minutes and 20 minutes, 30 minutes orless, 20 minutes or less, 15 minutes or less, 10 minutes or less).

After the calcium phosphate composition has been isolated and purified,the composition can be subjected to a further heat treatment to adjustthe distribution of phases and/or the morphology of the productcomposition. In some embodiments, for example, the calcium phosphatecomposition that is produced can be heated at a temperature of fromabout 40° C. to about 1200° C. (e.g., from about 40° C. to about 1200°C., from about 75° C. to about 1200° C., from about 100° C. to about1200° C., from about 150° C. to about 250° C., from about 150° C. toabout 1200° C., from about 180° C. to about 220° C., from about 250° C.to about 1200° C., from about 350° C. to about 1200° C., from about 450°C. to about 1200° C., from about 550° C. to about 1200° C., from about600° C. to about 1200° C., from about 650° C. to about 1200° C., fromabout 700° C. to about 1200° C., from about 750° C. to about 1200° C.,from about 775° C. to about 1200° C., from about 800° C. to about 1200°C., from about 850° C. to about 950° C., from about 850° C. to about1200° C., from about 900° C. to about 1200° C., from about 950° C. toabout 1200° C., from about 1000° C. to about 1200° C., from about 1050°C. to about 1200° C., from about 1100° C. to about 1200° C.). Heating inany of the above temperature ranges can be performed for a time periodfrom about 0.25 hours to about 5 hours (e.g., from about 1.5 hours toabout 5 hours, from about 1 hour to about 3 hours, from about 1.5 hoursto about 2.5 hours,).

V. Calcium Phosphate Compositions

A wide variety of calcium phosphate compositions can be produced usingthe synthetic methods disclosed herein, and by exercising suitablecontrol over the various reaction conditions and reagents discussedabove. In general, in addition to producing non-functionalized calciumphosphate product compositions, the methods disclosed herein can also beused to produce substituted calcium phosphate compositions featuring oneor more substituents, including but not limited to halide groups andhydroxide groups. Suitable halides can include, for example, fluoride,chloride, bromide and iodide. Calcium phosphate compositions cangenerally include one or more halide substituents and/or one or morehydroxide substituents. It should be understood that the followingdiscussion applies equally to substituted calcium phosphate compositionsand unsubstituted calcium phosphate compositions unless expressly statedotherwise.

Examples of calcium phosphate compositions that can be produced usingthe methods disclosed herein include, but are not limited to, calciumdihydrogen phosphate, calcium hydrogen phosphate, tricalcium phosphate,hydroxyapatite, fluorapatite, chlorapatite, apatite, octacalciumphosphate, biphasic calcium phosphate, tetracalcium phosphate,β-tricalcium phosphate, and amorphous calcium phosphate. In someembodiments, the calcium phosphate compositions produced include one ormore calcium phosphates selected from the group consisting ofhydroxyapatite, β-tricalcium phosphate, and amorphous calcium phosphate.

In some embodiments, the calcium phosphate compositions produced have amolar percentage of amorphous calcium phosphate from 0% to 100% (e.g.,from 0% to about 30%, from about 30% to about 70%, from about 70% to100%, from about 45% to about 55%, from about 25% to about 35%). Incertain embodiments, the calcium phosphate compositions consist entirelyof amorphous calcium phosphate. In some embodiments, the calciumphosphate compositions produced have a molar percentage of β-tricalciumphosphate from 0% to 100% (e.g., from 0% to about 30%, from about 30% toabout 70%, from about 70% to 100%, from about 5% to about 15%, fromabout 25% to about 35%, from about 30% to about 40%, from about 45% toabout 55%). In certain embodiments, the calcium phosphate compositionsconsist entirely of β-tricalcium phosphate. In some embodiments, thecalcium phosphate compositions produced have a molar percentage ofhydroxyapatite from 0% to 100% (e.g., from 0% to about 30%, from about30% to about 70%, from about 70% to 100%, from about 5% to about 15%,from about 10% to about 20%, from about 55% to about 65%, from about 85%to about 90%, from about 95% to 100%). In certain embodiments, thecalcium phosphate compositions consist entirely of hydroxyapatite.

(1) Monophasic Calcium Phosphates

In some embodiments, the calcium phosphate composition producedaccording to the methods disclosed herein is a monophasic calciumphosphate composition (MpCP). The monophasic calcium phosphatecomposition can include a calcium phosphate compound selected from thegroup consisting of calcium dihydrogen phosphate, calcium hydrogenphosphate, tricalcium phosphate, hydroxyapatite, fluorapatite,chlorapatite, apatite, octacalcium phosphate, biphasic calciumphosphate, tetracalcium phosphate, β-tricalcium phosphate, and amorphouscalcium phosphate.

(2) Biphasic Calcium Phosphates

In some embodiments, the calcium phosphate composition producedaccording to the methods disclosed herein is a biphasic calciumphosphate composition (BpCp). In some embodiments, the biphasic calciumphosphate composition includes two calcium phosphate compounds selectedfrom the group consisting of calcium dihydrogen phosphate, calciumhydrogen phosphate, tricalcium phosphate, hydroxyapatite, fluorapatite,chlorapatite, apatite, octacalcium phosphate, biphasic calciumphosphate, tetracalcium phosphate, β-tricalcium phosphate, and amorphouscalcium phosphate.

In some embodiments, the biphasic calcium phosphate composition includeshydroxyapatite and β-tricalcium phosphate. The molar ratio ofhydroxyapatite to β-tricalcium phosphate can be from about 1:100 toabout 50:50 (e.g., from about 10:90 to about 50:50, from about 20:80 toabout 50:50, from about 30:70 to about 50:50, from about 40:60 to about50:50). In some embodiments, the molar ratio of hydroxyapatite toβ-tricalcium phosphate is from about 100:1 to about 50:50 (e.g., fromabout 90:10 to about 50:50, from about 80:20 to about 70:30, from about60:40 to about 50:50, from about 80:20 to about 95:5, from about 55:45to about 75:25, about 90:10, about 60:35).

In some embodiments, the biphasic calcium phosphate composition includeshydroxyapatite and amorphous calcium phosphate. The molar ratio ofhydroxyapatite to amorphous calcium phosphate can be from about 1:100 toabout 50:50 (e.g., from about 10:90 to about 50:50, from about 20:80 toabout 50:50, from about 30:70 to about 50:50, from about 40:60 to about50:50). In some embodiments, the molar ratio of hydroxyapatite toamorphous calcium phosphate is from about 100:1 to about 50:50 (e.g.,from about 90:10 to about 50:50, from about 80:20 to about 70:30, fromabout 60:40 to about 50:50).

In some embodiments, the biphasic calcium phosphate composition includesβ-tricalcium phosphate and amorphous calcium phosphate. The molar ratioof β-tricalcium phosphate to amorphous calcium phosphate can be fromabout 1:100 to about 50:50 (e.g., from about 10:90 to about 50:50, fromabout 20:80 to about 50:50, from about 30:70 to about 50:50, from about40:60 to about 50:50). In some embodiments, the molar ratio ofβ-tricalcium phosphate to amorphous calcium phosphate is from about100:1 to about 50:50 (e.g., from about 90:10 to about 50:50, from about80:20 to about 70:30, from about 60:40 to about 50:50).

(3) Triphasic Calcium Phosphates

In some embodiments, the calcium phosphate composition producedaccording to the methods disclosed herein is a triphasic calciumphosphate composition (TpCP). In some embodiments, the triphasic calciumphosphate composition includes three calcium phosphate compoundsselected from the group consisting of calcium dihydrogen phosphate,calcium hydrogen phosphate, tricalcium phosphate, hydroxyapatite,fluorapatite, chlorapatite, apatite, octacalcium phosphate, biphasiccalcium phosphate, tetracalcium phosphate, β-tricalcium phosphate, andamorphous calcium phosphate.

In some embodiments, the triphasic calcium phosphate compositionincludes hydroxyapatide, β-tricalcium phosphate, and amorphous calciumphosphate in a molar ratio of about 10:35:55, about 10:40:50, about20:30:50, about 20:35:45, about 15:30:55, about 15:40:45, about15:35:50, about 5:65:30, about 5:60:35, about 15:55:30, about 15:60:25,about 10:55:35, about 10:65:25, or about 10:60:30.

In certain embodiments where the triphasic calcium phosphate compositionincludes hydroxyapatide, β-tricalcium phosphate, and amorphous calciumphosphate, the fraction of each of the compounds in the composition canbe from 0% to about 95% (e.g., from 10% to about 80%, from 20% to about70%, from 30% to about 60%, from 30% to about 90%, from 20% to about90%, from 10% to about 90%, from 30% to about 70%, from 20% to about70%, from 10% to about 70%, from 20% to about 50%, from 10% to about50%).

(4) Physical Properties

In general, using the methods disclosed herein calcium phosphatecompositions can be produced with a relatively wide range of specificsurface areas. For example, the compositions can have specific surfaceareas from about 30 m²/g to about 90 m²/g (e.g., from about 40 m²/g toabout 90 m²/g, from about 50 m²/g to about 90 m²/g, from about 60 m²/gto about 90 m²/g, from about 70 m²/g to about 90 m²/g, from about 80m²/g to about 90 m²/g. In some embodiments, the specific surface area ofthe compositions is 50 m²/g or more (e.g., 60 m²/g or more, 70 m²/g ormore, 80 m²/g or more, 85 m²/g or more, 90 m²/g or more).

The average particle size (i.e., the average size of the maximumparticle dimension) of the calcium phosphate composition that isproduced, as measured using scanning electron microscopy, is from about100 nm to about 50 μm (e.g., from about 500 nm to about 50 μm, fromabout 1 μm to about 50 μm, from about 5 μm to about 50 μm, from aboutfrom about 10 μm to about 50 μm, from about 15 μm to about 30 μm, fromabout 20 μm to about 30 μm, from about 20 μm to about 50 μm, from about30 μm to about 50 μm, from about 40 μm to about 50 μm).

In certain embodiments, the specific porosity of the calcium phosphatecompositions produced as disclosed herein is between about 0.1 cm³/g andabout 0.25 cm³/g (e.g., between about 0.1 cm³/g and about 0.17 cm³/g,between about 0.15 cm³/g and about 0.25 cm³/g, between about 0.15 cm³/gand 0.17 cm³/g, larger than about 0.15 cm³/g).

The particles of the calcium phosphate compositions produced asdisclosed herein have an aspect ratio defined as the ratio of themaximum overall particle dimension in any direction to the maximumparticle dimension in any direction orthogonal to the maximum overallparticle dimension. By adjusting the final pH of the product slurry instep 108 and heating of the calcium phosphate composition that isproduced, particles with a wide variety of different aspect ratios canbe produced. For example, in some embodiments, the mean aspect ratio ofthe calcium phosphate composition that is produced is 5:1 or more (e.g.,10:1 or more, 25:1 or more, 50:1 or more, 100:1 or more, 200:1 or more,300:1 or more, 500:1 or more, 750:1 or more).

The molar ratio of calcium and dihydrogen phosphate ions, the final pHof the product slurry, and post-purification heating of the calciumphosphate composition produced also influences the crystallinity of thecomposition. In certain embodiments, for example, the crystallinity ofthe calcium phosphate composition is greater than 50% (e.g., greaterthan 60%, greater than 70%, greater than 80%, greater than 90%, greaterthan 95%, greater than 98%, greater than 99%).

EXAMPLES

The following specific examples are intended to further illustrateaspects of the methods and compositions disclosed herein, but are notintended to limit the scope of the disclosure in any manner.

The examples include measurements of various physical properties ofcalcium phosphate compositions that have been produced. To measure thephysical properties, a variety of techniques and instruments were used.Analyses of the compositions was conducted using X-ray diffraction (XRD)to determine the ratio of phases in the composition prior to heattreatment and after the heat treatment. The compositions were analyzedon a Philips diffractometer with radiation Cu-Kα operated at 40 kW and20 mA, with a scan rate of 0.06 degrees/sec. Calculations of thepercentages of the calcium phosphates (e.g., hydroxyapatite,β-tricalcium phosphate, and amorphous calcium phosphate in BpCP and TpCPcompositions) were performed based on the integration of the areas underthe curves of the XRD spectra. Crystallinity measurements were alsodetermined using XRD analysis.

Laser diffraction, scanning electron microscopy, and nitrogen pycnometrymeasurements were performed on compositions with nominal particle sizesbetween 38 μm and 53 μm, isolated using molecular sieves, to determineparticle size distributions. Measurements of particle size distributionwere also performed for certain compositions using a laser diffractionmethod in combination with a particle size analyzer (a CILAS 1064instrument, available from CILAS, Orleans, France).

Analyses of particle morphology were also performed using scanningelectron microscopy (SEM) (a JEOL 6300 scanning electron microscope,available from JEOL USA, Peabody, Mass.) operated at 25 kV. Chemicalmicroanalysis was performed using energy dispersive X-ray analysis(EDXA) to measure the Ca/P ratio in the compositions, and to identifypotential contaminants. The specific surface area of the calciumphosphates was determined by nitrogen adsorption in a QuantachromeAutosorb instrument (available from Quantachrome, Boynton Beach, Fla.).

Example 1. Preparation of Biphasic Calcium Phosphate Composition (90%Hydroxyapatite, 10% β-Tricalcium Phosphate) Step 1: Preparation of aCalcium Hydroxide Mixture

Water (2 L) was cooled to a temperature of between about 20 to 26° C.,then reactive calcium oxide (509.3 g, 9.08 mol, 95% purity, prepared asdiscussed herein) was added with stirring. After completion of thereaction, the resulting calcium hydroxide mixture was filtered through a100 mesh (0.149 mm) filter and cooled to 22° C.

Step 2: Preparation of a Calcium Dihydrogen Phosphate Mixture

Phosphoric acid (29%, 2 L) was cooled to a temperature of 10° C. andadded to a portion of the calcium hydroxide mixture of Step 1 at a rateof 30 g/min with stirring at 200 rotations per minute. The resultingcalcium dihydrogen phosphate mixture had a pH of 3.

Step 3: Preparation of an Amorphous Calcium Phosphate

The calcium dihydrogen phosphate mixture was added to another portion ofthe calcium hydroxide mixture at a rate of 30 g/min with stirring at 200rotations per minute, and the resulting reaction mixture had pH of 12.The reaction mixture was then dried at 200° C. to produce amorphouscalcium phosphate. The aggregated particles were mechanically broken up,and the resulting particles sieved at 325 mesh (0.044 mm) for X-raydiffraction analysis.

Step 4: Preparation of a Biphasic Calcium Phosphate Composition (90%Hydroxyapatite, 10% β-Tricalcium Phosphate)

A fraction of the amorphous calcium phosphate was calcined at 900° C.for 4.0 hours to produce biphasic calcium phosphate (90% hydroxyapatite,10% β-tricalcium phosphate), which was analyzed using X-ray diffraction.

Example 2. Preparation of Triphasic Calcium Phosphate (15%Hydroxyapatite, 35% β-Tricalcium Phosphate, 50% Amorphous CalciumPhosphate) Step 1: Preparation of a Calcium Hydroxide Mixture

Water (2 L) was cooled to a temperature of between 20 to 26° C., thenreactive calcium oxide (509.3 g, 9.08 mol, 95% purity, preparedaccording to procedures provided in U.S. Patent Application No.62/232,999) was added with strong agitation. After completion of thereaction, the resulting calcium hydroxide mixture was filtered through a100 mesh (0.149 mm) filter and cooled to 22° C.

Step 2: Preparation of a Calcium Dihydrogen Phosphate Mixture

Phosphoric acid (31.6%, 2 L) at a temperature of 22° C. was added to aportion of the calcium hydroxide mixture from Step 1, at a rate of 30g/min with stirring at 200 rotations per minute. The resulting calciumdihydrogen phosphate mixture had a pH of 2.

Step 3: Preparation of a Triphasic Calcium Phosphate (15%Hydroxyapatite, 35% β-Tricalcium Phosphate, 50% Amorphous CalciumPhosphate)

The calcium dihydrogen phosphate mixture was added to another portion ofthe calcium hydroxide mixture at a rate of 30 g/min with stirring at 200rotations per minute at a pH of 11.

The products were dried at 200° C. to produce triphasic calciumphosphate (15% hydroxyapatite, 35% β-tricalcium phosphate, 50% amorphouscalcium phosphate). The aggregated particles were mechanically brokenup, and the resulting particles sieved at 325 mesh (0.044 mm) for X-raydiffraction analysis.

Example 3. Preparation of a Biphasic Calcium Phosphate (65%Hydroxyapatite, 35% β-Tricalcium Phosphate)

A fraction of the amorphous calcium phosphate (prepared according to theprocedure of Example 2, Steps 1-3) was calcined at 900° C. for 4.0 hoursto produce biphasic calcium phosphate (90% hydroxyapatite, 10%β-tricalcium phosphate), which was analyzed using x-ray diffraction.

Example 4. Preparation of Triphasic Calcium Phosphate (10%Hydroxyapatite, 60% β-Tricalcium Phosphate, 30% Amorphous CalciumPhosphate) Step 1: Preparation of a Calcium Hydroxide Mixture

Water (4 L) was cooled to a temperature of between 40 to 60° C., thenreactive calcium oxide (509.3 g, 9.08 mol, 95% purity, preparedaccording to procedures discussed herein) was added with strongagitation. After completion of the reaction, the resulting calciumhydroxide mixture was filtered through a 100 mesh (0.149 mm) filter andcooled to 22° C.

Step 2: Preparation of a Calcium Dihydrogen Phosphate Mixture

Phosphoric acid (34.0%, 3 L) at a temperature of 22° C. was added to aportion of the calcium hydroxide mixture from Step 1 at a rate of 30g/min with stirring at 200 rotations per minute. The resulting calciumdihydrogen phosphate mixture had a pH of 1.

Step 3: Preparation of a Triphasic Calcium Phosphate (10%Hydroxyapatite, 60% fi-Tricalcium Phosphate, 30% Amorphous CalciumPhosphate)

The calcium dihydrogen phosphate mixture from Step 2, was added toanother portion of the calcium hydroxide mixture of Step 1, at a rate of30 g/min with stirring at 200 rotations per minute, and the resultingreaction mixture had a pH of 10. The reaction mixture was then dried at200° C. to produce triphasic calcium phosphate (10% hydroxyapatite, 60%β-tricalcium phosphate, 30% amorphous calcium phosphate). The aggregatedparticles were mechanically broken up, and the resulting particlessieved at 325 mesh (0.044 mm) for X-ray diffraction analysis.

Table 1 shows the properties of triphasic calcium phosphate (10%hydroxyapatite, 60% β-tricalcium phosphate, 30% amorphous calciumphosphate). The particle size distribution was measured by laserdiffraction using the Fraunhofer method and scanning electronmicroscopy. The size of the smallest particle was calculated by theScherrer method using X-ray diffraction. The aspect ratio was measuredby scanning electron microscopy. The specific surface area, microporeand mesopore volumes, and average diameter of pores were determined bynitrogen pycnometry.

TABLE 1 Properties of Triphasic Calcium Phosphate (10% hydroxyapatite,60% β-tricalcium phosphate, 30% amorphous calcium phosphate) PropertyValue(s) Particle size distribution (μm) 3.54 (10^(th) 20.07 (50^(th)53.11 (90^(th) percentile) percentile) percentile) Average particlediameter (μm, 24.89 laser diffraction) Particle size distribution (μm, 5-45 SEM) Size of smallest particle 14 nm Aspect ratio (SEM) 1.5-2.5Specific surface area (m²/g) 75 ± 2 Micro and mesopores volumes 16 ± 1(10⁻² cm³/g) Average diameter of pores 18 ± 1 (angstroms) CrystallinityIndex Approximately 25%

Example 5. Alternative Preparation of a Hydroxyapatite Composition Step1: Preparation of a Calcium Hydroxide Mixture

Water (5 L) was cooled to a temperature of between 40 to 60° C., thenreactive calcium oxide (436.7 g, 7.79 mol, 95% purity, preparedaccording to procedures provided in U.S. Patent Application No.62/232,999) was added with strong agitation. After completion of thereaction, the resulting calcium hydroxide mixture was filtered through a100 mesh (0.149 mm) filter and cooled to 22° C.

Step 2: Preparation of a Calcium Dihydrogen Phosphate Mixture

Phosphoric acid (30.5%, 5 L) at a temperature of 22° C. was added to thecalcium hydroxide mixture at a rate of 30 g/min with stirring at 200rotations per minute. The resulting calcium dihydrogen phosphate mixturehad a pH of 1.

Step 3: Preparation of the Hydroxyapatite Composition

The calcium dihydrogen phosphate mixture of Step 2 was added to thefirst calcium hydroxide mixture of Step 1 at a rate of 30 g/min withstirring at 200 rotations per minute, and the resulting reaction mixturehad a pH of 7. The reaction mixture was then dried at 200° C. Theresulting aggregated particles were mechanically broken up, and theparticles were sieved at 325 mesh (0.044 mm). The particles were thencalcined at 950° C. for 4 hours to produce the hydroxyapatitecomposition, which was analyzed using X-ray diffraction.

Example 6. Amorphous Calcium Phosphate

Another sample of amorphous calcium phosphate was prepared as discussedabove in connection with Example 1, and its properties were measured.Table 2 summarizes the results of the measurements. The particle sizedistribution was measured by laser diffraction using the Fraunhofermethod and scanning electron microscopy. The size of the smallestparticle was calculated by the Scherrer method using X-ray diffraction.The aspect ratio was measured by scanning electron microscopy. Thespecific surface area, micropore and mesopore volumes, and averagediameter of pores were determined by nitrogen pycnometry.

TABLE 2 Properties of Amorphous Calcium Phosphate Property Value(s)Particle size distribution (μm) 3.02 (10^(th) 12.76 (50^(th) 29.49(90^(th) percentile) percentile) percentile) Average particle diameter(μm, 14.81 laser diffraction) Particle size distribution (μm, 10-45 SEM)Size of smallest particle 14 nm Aspect ratio (SEM) 1.5-2.5 Specificsurface area (m²/g) 66 ± 2 Micro and mesopores volumes 13 ± 1 (10⁻²cm³/g) Average diameter of pores 17 ± 1 (angstroms) Crystallinity IndexApproximately 20%

FIG. 4 is an X-ray diffractogram of a sample of amorphous calciumphosphate (curve 400) superimposed with an X-ray diffractogram ofamorphous calcium phosphate after carbon dioxide saturation (curve 402)expressed as intensity (CPS) as a function of scattering angle (20). Asignificant difference is observed between the peak intensities in plots400 and 402.

FIGS. 5A and 5B are SEM photomicrographs of amorphous calcium phosphateat a magnification factor of 500 and a magnification factor of 1500,respectively. The images show that the amorphous calcium phosphateconsists of small, irregularly-shaped particles and plates formingagglomerates. Nanometric particles can also be observed, which areadhered to larger irregular particles forming clusters. These clusters,together with the observed porosity, are believed to contribute to thehigh surface area of the amorphous calcium phosphate.

Example 7. Triphasic Calcium Phosphate

A sample of triphasic calcium phosphate consisting of 10%hydroxyapatite, 60% β-tricalcium phosphate, and 30% amorphous calciumphosphate, was prepared using the methods discussed above in connectionwith Example 4, and its properties were measured. Table 3 summarizes theresults. Particle size measurements and distribution were measured bylaser diffraction (CILAS) and confirmed by SEM measurements. The size ofthe smallest particle was calculated by the Scherrer method using X-raydiffraction. The aspect ratio was measured by scanning electronmicroscopy. The specific surface area, micropore and mesopore volumes,and average diameter of pores were determined by nitrogen pycnometry.

TABLE 3 Properties of Triphasic Calcium Phosphate (10% Hydroxyapatite,60% β-Tricalcium Phosphate, 30% Amorphous Calcium Phosphate) PropertyValue(s) Particle size distribution (μm) 3.54 (10^(th) 20.07 (50^(th)53.11 (90^(th) percentile) percentile) percentile) Average particlediameter (μm, 24.89 laser diffraction) Particle size distribution (μm, 5-45 SEM) Size of smallest particle 14 nm Aspect ratio (SEM) 1.5-2.5Specific surface area (m²/g) 75 ± 2 Micro and mesopores volumes 16 ± 1(10⁻² cm³/g) Average diameter of pores 18 ± 1 (angstroms)

The specific surface area, volume and average diameter of micro andmesopores reported in Table 3 were determined using the BET technique.These data show a significant difference specific surface area, volume,average diameter and distribution of pores between tri-phasic calciumphosphate and biphasic calcium phosphate. The surface area of thetriphasic calcium phosphate was calculated using the BET equation. Asthe BET method with nitrogen does not uniformly provide an accurateestimate for the calculation of surface areas on materials that haveisotherms of the type corresponding to this sample, these resultsconfirm qualitatively that the particles had a large surface area. FIG.6 is a photomicrograph produced using a scanning electron microscope,showing a portion of the triphasic calcium phosphate composition thatwas produced.

Example 8. Biphasic Calcium Phosphate

A sample of biphasic calcium phosphate consisting of 90% hydroxyapatiteand 10% β-tricalcium phosphate was measured, with the measurementresults summarized in Table 4.

TABLE 4 Properties of Biphasic Calcium Phosphate (90% Hydroxyapatite,10% β-Tricalcium Phosphate) Property Value(s) Particle size distribution(μm) 4.3 (10^(th) 17.7 (50^(th) 39.8 (90^(th) percentile) percentile)percentile) Average particle diameter (μm, 20.3 laser diffraction)Particle size distribution (μm, 20-50 SEM) Size of smallest particle 16nm Aspect ratio (SEM) 1.5-2.5 Specific surface area (m²/g)  40 ± 2 Microand mesopores volumes  9 ± 1 (10⁻² cm³/g) Average diameter of pores 104± 4 (angstroms)

The particle size distributions in Table 4 were determined from SEMimages using the Scherrer formula, and from laser diffraction (CILAS)measurements. Comparison between the size distributions provided by theSEM and laser diffraction showed a significant difference between thesetwo results possibly arising from particle clusters. One possibleexplanation is due to particle agglomeration due to zeta potential,e.g., the agglutination factor by surface electric charges and aprobable measurement sizes of agglomerates rather than individualparticles. The density of particles was measured by a nitrogenpycnometer and approached the theoretical density of hydroxyapatite(e.g., 3.2 g/cm³), when the porosity is extremely low.

The specific surface area, volume and average diameter of micro- andmesopores were determined using the BET method. The surface area wascalculated by the BET equation (an average of three samples beinganalyzed). It should be noted that the BET method with nitrogen does notuniformly provide an accurate estimate for the calculation of surfaceareas on all materials. Therefore, while these results verify that theparticles had a large surface area, they are most useful wheninterpreted qualitatively.

FIGS. 7A and 7B are SEM images of the biphasic calcium phosphate sampleat magnifications of 50X (FIG. 7A) and 5000X (FIG. 7B). Thesemicrographs demonstrate that the biphasic calcium phosphate powderincludes particles and small plates forming clusters with irregularshapes. Nanoscale particles were observed adhering to larger particleswhich may increase the surface area of the particles. The distributionof sizes of the biphasic calcium phosphate composition particlesobtained from screening between 38 μm and 53 μm was confirmed bymeasurements made by SEM.

Example 9. X-Ray Diffraction Measurements

Table 5 shows X-ray diffraction peak values, in units of θ, andassociated intensities for calcium phosphate compositions prepared inExamples 1-5.

TABLE 5 X-Ray Diffraction Peak Values and Intensities Calcium PhosphateComposition θ Values (with CPS intensity in parentheses) AmorphousCalcium 26.1 (292), 26.7 (179), 32 (204), 31.9 (570), 32.2 Phosphate(ACP) (583), 34.3 (184), 40.2 (140), 46.8 (155), 49.7 (191). BiphasicCalcium 21.9 (168), 22.9 (140), 25.5 (80), 25.9 (660), 28.2 Phosphate(90% HA, (180), 29 (320), 31.9 (1820), 32.3 (1290), 33.0 10% β-TCP;(1146), 34.2 (475), 35.7 (60), 37.4 (1280), 39.3 Example 1) (138), 39.8(430), 40.5 (60), 42.1 (137), 43.9 (110), 45.3 (96), 46.8 (515), 48.2(221), 48.7 (55), 49.6 (580). Triphasic Calcium 20.9 (142), 23.1 (88),25.8 (165), 26.5 (373), 26.7 Phosphate (15% HA, (368), 28.8 (212), 29.4(487), 30.2 (233), 32.1 35% β-TCP, 50% (360), 32.3 (331), 32.8 (300),33.4 (178), 34.1 ACP; Example 2) (509), 36.0 (120), 39.4 (122), 40.1(148), 43.2 (120), 47.2 (255), 48.5 (182), 49.2 (150), 49.5 (151).Biphasic Calcium 21.9 (130), 23.0 (140), 25.6 (78), 26.0 (558), 28.2Phosphate (65% HA, (180), 29.1 (260), 31.2 (50), 31.9 (1420), 32.3 35%β-TCP; (1260), 33.0 (860), 34.2 (400), 35.8 (92), 37.5 Example 3)(1640), 39.3 (119), 40.0 (320), 40.7 (55), 42.2 (115), 44.0 (80), 45.5(80), 46.8 (443), 48.2 (212), 48.8 (85), 49.7 (480). Triphasic Calcium13.0 (190), 26.0 (1010), 28.7 (290), 30.1 (1190), Phosphate (10% HA,32.0 (288), 32.3 (465), 32.9 (594), 36.0 (209), 60% β-TCP, 30% 40.0(230), 41.0 (200), 42.2 (190), 47.7 (212), ACP; Example 4) 49.8 (307),53.2 (317). Hydroxyapatite 21.9 (190), 23.1 (150), 25.6 (90), 26.0(630), 28.2 Composition (210), 29.1 (420), 32.9 (2140), 32.3 (1320),33.0 (Example 5) (1512), 34.2 (495), 35.7 (140), 37.5 (945), 39.3 (120),39.9 (580), 40.6 (54), 42.1 (144), 43.9 (107), 44.4 (45), 45.4 (108),46.8 (655), 48.2 (303), 48.8 (109), 49.6 (618).

Example 10. Synthesis of Hydroxyapatite-Containing Compositions

A series of calcium phosphate compositions designated CP14-CP28 wereprepared using the methods disclosed herein. A solution of 250 kg ofreactive CaO dissolved in 2500 L of deionized water was prepared,agitating for 20 minutes to complete dissolution, forming a Ca(OH)₂solution. The solution was filtered using mesh sieves #100 (149 μm),#170 (88 μm), and #270 (53 μm). A 50% phosphoric acid solution was alsoprepared by dissolving 406 kg of solid phosphoric acid in 406 kg ofdeionized water. The phosphoric acid solution was added to the Ca(OH)₂solution at a rate of 6.8 kg/min. with constant agitation over a totaltime period of 120 minutes. The final pH of the calcium dihydrogenphosphate slurry that formed was 1.66.

A second Ca(OH)₂ solution was prepared by dissolving 250 kg of reactiveCaO in 3000 kg of deionized water over a period of 20 minutes withconstant agitation. The second Ca(OH)₂ solution was filtered usingsieves #100 (149 μm), #170 (88 μm), and #270 (53 μm).

The second Ca(OH)₂ solution was then added to the calcium dihydrogenphosphate slurry, with controlled agitation, at a rate of 17.4 kg/min.for 150 minutes. The final pH of the resulting slurry was 7.4. Agitationof the slurry was continued for an additional 30 minutes withoutaddition of any further reagents until rheological equilibrium wasachieved.

The samples were dried as discussed above. During drying, samplesCP14-CP20 were subjected to thermal shock to adjust the porosity andspecific surface area. Sample CP14 was sieved using a 325 mesh filter toyield a sample with a mean particle size of 44 microns. SamplesCP17-CP19 were also sieved to yield samples with a distribution ofparticles within a range of 0.3 mm to 3.35 mm. Sample CP20 was subjectto comminution to yield a sample with particle sizes between 2 mm and 4mm. All samples were first dried in a gas oven at 200° C., and then inan electric oven at 300° C. for 6 hours. Samples CP15 and CP16 were thensubjected to an additional heat treatment; CP15 was heated to atemperature of 500° C. for a time of 1 hour, while CP16 was heated to atemperature of 600° C. for a time of 1 hour.

SEM images of several of the samples were obtained. FIGS. 8A-8C are SEMimages of sample CP14 at different magnifications, FIGS. 9A and 9B areSEM images of sample CP15, FIGS. 10A and 10B are SEM images of sampleCP16, FIG. 11 is a SEM image of sample CP19, and FIG. 12 is a SEM imageof sample CP20. FIG. 13 is a plot showing x-ray scattering from sampleCP14, and FIG. 14 is a plot showing infrared absorption measurements onsample CP14.

Specific surface area measurements were performed on samples CP14-CP19using an Autosorb-6B instrument and degasser (from QuantachromeInstruments, Germany), using the BET method. Nitrogen was used foradsorption and desorption measurements. Measured specific surface areas(in units of m²/g for samples CP14-CP19 were 62.4, 47.5, 39.7, 60.5,61.5, and 60.8, respectively. Specific porosity measurements were alsoperformed using the same analysis method; for each of the samples,specific porosity was between 25 cm³/g and 35 cm³/g.

Table 6 shows reaction conditions for and properties for the variousHA-containing samples. In Table 6, data in the “Post-Isol. Treatment”column indicates temperatures and duration of any post-isolationprocessing of the samples. Data in the “Phases” column indicatesidentified phases in the samples, data in the “Cryst. (%)” columnindicates measured crystallinity values for the samples, and data in the“Surface Area (m²/g)” column corresponds to surface area measurementsfor the samples, in units of m²/g.

TABLE 6 Properties of samples CP14-CP27 Post-Isol. Cryst. Surface AreaSample Treatment Phases (%) (m²/g) CP14 200° C. 27% DCPA 61.64 73% HACP15 500° C., 1 hour 14% β-TCPM 59.88 86% HA CP16 600° C., 1 hour 15%β-TCPM 57.44 85% HA CP17 18% DCPA 58.44 82% HA CP19 30% DCPA 55.3649.769 70% HA CP20 45% DCPA 68.11 30.917 55% HA CP22 HA 56.30 CP23 45%DCPA 68.11 30.917 55% HA CP24 β-TCPM 64.67 23.756 HA CP27 HA 59.0747.063 CP28 10% DCPA 64.44 85.191 90% HA

Example 11. Synthesis of Monophasic and Multiphasic Compositions

A series of calcium phosphate compositions designated CP02-CP11 andRWK03-RWK21 were prepared using the general methods disclosed herein.

To prepare samples CP02-CP11, a solution of 163 kg of reactive CaOdissolved in 1800 L of deionized water was prepared, agitating for 20minutes to complete dissolution, forming a Ca(OH)₂ solution. Thesolution was filtered using mesh sieves #100 (149 μm) and #140 (105 μm).A 50% phosphoric acid solution was also prepared by dissolving 512 kg ofsolid phosphoric acid in 1536 kg of deionized water. The phosphoric acidsolution was added to the Ca(OH)₂ solution at a rate of 12.8 kg/min.with constant agitation over a total time period of 40 minutes. Thefinal pH of the calcium dihydrogen phosphate slurry that formed was2.30.

A second Ca(OH)₂ solution was prepared by dissolving 250 kg of reactiveCaO in 3000 kg of deionized water over a period of 20 minutes withconstant agitation. The second Ca(OH)₂ solution was filtered usingsieves #100 (149 μm) and #140 (105 μm).

The second Ca(OH)₂ solution was then added to the calcium dihydrogenphosphate slurry, with controlled agitation, for 150 minutes. Agitationof the slurry was stopped after addition of the second Ca(OH)₂ solution.

The samples were dried as discussed above at a temperature between 200°C. and 400° C. Certain samples (CP02, CP03, CP04, CP06, CP08, CP10, andCP11) were then subjected to post-isolation heating at a temperature ofbetween 700-800° C. for a time period of between 1-2 hours, as follows:CP02, 700° C., 1.5 hours; CP03, 800° C., 2 hours; CP04, 700° C., 1 hour;CP06, 800° C., 1 hour; CP08, 800° C., 1 hour; CP10, 700° C., 1 hour; andCP11, 800° C., 2 hours.

Properties of the various samples, measured as discussed above, areshown in Table 7. In Table 7, data in the “Final pH” column indicate thepH of the product solution after the second Ca(OH)₂ solution has beenadded, and data in the “Post-Isol. Treatment” column correspond toheating temperatures and times to which the calcium phosphate productswere subjected following isolation. Data in the “Phases” column indicatethe identified phases in various samples, and data in the “Cryst. (%)”column correspond to measured crystallinity values for the samples.

TABLE 7 Properties of samples CP02-CP11 Final Cryst. Sample pHPost-Isol. Treatment Phases (%) CP02 700° C., 1 hour HA 77.81 CP03 7 800° C., 2 hours HA 94.52 CP04 7 700° C., 1 hour HA 86.65 CP05 42% HA57.78 58% DCPD CP06 7 800° C., 1 hour 25% HA 89.30 75% β-TCP CP07 37% HA57.76 63% DCPD CP08 800° C., 1 hour 36% HA 90.87 64% β-TCP CP09 7 400°C. HA 53.67 CP10 7 700° C., 1 hour HA 71.52 CP11 7  800° C., 2 hours HA93.87

To prepare samples RWK03-RWK21, a solution of 163 kg of reactive CaOdissolved in 1630 L of deionized water was prepared, agitating for 20minutes to complete dissolution, forming a Ca(OH)₂ solution. Thesolution was filtered using mesh sieves #100 (149 μm). A 50% phosphoricacid solution was also prepared by dissolving 458 kg of solid phosphoricacid in 916 kg of deionized water. The phosphoric acid solution wasadded to the Ca(OH)₂ solution at a rate of 11.45 kg/min. with constantagitation over a total time period of 40 minutes. The final pH of thecalcium dihydrogen phosphate slurry that formed was 2.65.

A second Ca(OH)₂ solution was prepared by dissolving 250 kg of reactiveCaO in 2500 kg of deionized water over a period of 20 minutes withconstant agitation. The second Ca(OH)₂ solution was filtered usingsieves #100 (149 μm).

The second Ca(OH)₂ solution was then added to the calcium dihydrogenphosphate slurry, with controlled agitation, for 150 minutes. Agitationof the slurry was stopped after addition of the second Ca(OH)₂ solution.The samples were dried as discussed above at a temperature between 200°C. and 400° C.

Properties of the various samples, measured as discussed above, areshown in Table 8. In Table 8, data in the “Final pH” column indicate thepH of the product solution after the second Ca(OH)₂ solution has beenadded, data in the “Phases” column indicate the identified phases invarious samples, and data in the “Surface Area (m²/g)” column correspondto measured surface values for the samples, in units of m²/g.

TABLE 8 Properties of samples RWK03-RWK21 Final Surface Area Sample pHPhases (m²/g) RWK03 6 DCPA 26.90 RWK04 12.97 CPP 15.34 β-TCP RWK07 13β-TCP 10.30 RWK08 13.02 β-TCP 11.79 RWK09 13.02 β-TCP 9.044 RWK10 13β-TCP 8.727 RWK11 13 β-TCP 8.253 RWK12 13 β-TCP 8.263 RWK13 12.98 β-TCP9.429 RWK14 12.99 DCPA 42.10 RWK15 12.96 DCPA 34.15 RWK16 12.86 DCPA48.97 RWK17 5.40 β-TCP 11.37 CPP RWK18 8.09 β-TCP 8.80 CPP RWK19 8.60β-TCP 9.143 CPP RWK20 8.73 β-TCP 3.673 CPP RWK21 9.29 β-TCP 2.271Ca₅(PO₄)₃(OH)

Example 12. Controlled Variation of Reaction Conditions

To investigate the effects of variations in stoichiometry on thechemical and physical properties of the calcium phosphate compositionsproduced using the methods disclosed herein, a large number of calciumphosphate compositions were prepared under varying conditions. Thereagents and conditions are summarized in Table 6 below.

TABLE 9 Summary of Reagents and Conditions for Controlled Synthesis Sam-Final Cryst. SSA ple pH Heating Phases (%) (m²/g) 1 7 700° C. - 1 hβ-TCP 96.35 2 7 800° C. - 1 h β-TCP 97.37 3 7 850° C. - 4 h β-TCP 99.304 7 900° C. - 1 h β-TCP 98.25 5 11  700° C. - 3.5 h 5% β-TCP 79.91 95%HA 6 11  700° C. - 2.5 h 5% β-TCP 80.38 95% HA 7 11 700° C. - 1 h 5%β-TCP 78.31 95% HA 8 7 950° C. - 1 h 5% β-TCP 96.74 95% HA 9 7 200° C.HA 49.94 10 7 800° C. - 2 h HA 91.48 11 7 200° C. 10% DCPA 54.10 90% HA12 7 400° C. - 1 h HA 53.67 13 7 650° C. - 1 h HA 71.52 14 7 700° C. - 1h HA 77.92 15 6 700° C. - 1 h HA 84.88 16 7 800° C. - 1 h 50% β-TCP88.08 20% HA 30% β-TCPM 17 7  950° C. - 3.5 h 60% β-TCP 99.13 40% β-TCPM18 7 200° C. 75% DCPD 73.05 15% DCPA 10% HA 19 7 200° C. 22% DCPD 48.2278% HA 20 7 1000° C. - 1 h  15% β-TCP 96.73 85% HA 21 12 800° C. - 1 h43% β-TCP 88.95 57% HA 22 11 200° C. 23% HA 74.87 77% DCPD 23 7 950°C. - 4 h 39% β-TCP 93.55 61% HA 24 7 200° C. HA 40.96 25 7 950° C. - 4 h21% β-TCP 96.42 79% HA 26 9 200° C. 60% DCPD 40.46 30% HA 10% DCPA 27 7800° C. - 1 h 22% HA 90.88 9.365 78% β-TCP 28 7 800° C. - 1 h 32% HA90.75 10.127 78% β-TCP 29 10 200° C. 50% DCPD 59.87 45% HA 5% DCPA 30 7200° C. 43% DCPA 55.14 57% HA 31 12 200° C. 70% DCPA 83.54 20% DCPD 10%HA 32 12 200° C. 60% HA 77.48 20% DCPD 20% DCPA 33 12 700° C. - 1 h 14%β-TCP 81.61 86% HA 34 6 200° C. 60% DCPD 74.80 25% DCPA 15% HA 35 6 250°C. 50% DCPA 66.01 30% DCPD 20% HA 36 6 200° C. HA 55.78 37 7 800° C. - 1h 28% HA 84.57 72% β-TCP 38 7 700° C. - 1 h HA 74.92 39 6 700° C. - 1 h5% β-TCP 79.95 95% HA 40 7  700° C. - 1.5 h 24% β-TCP 81.15 76% HA 41 7 700° C. - 1.5 h 90% HA 84.07 11.849 10% β-TCP 42 7 200° C. HA 51.8581.500 43 6 250° C. HA 50.72 44 7 700° C. - 1 h HA 78.23 45 7 750° C. -1 h 40% β-TCP 76.57 60% HA 46 11 200° C. 8% DCPA 50.97 92% HA 47 6 200°C. 10% DCPD 52.98 50% DCPA 40% HA 48 6.5  750° C. - 1.5 h 80% β-TCP90.54 20% β-TCPM 49 7 200° C. 30% HA 62.20 70% DCPA 50 6 200° C. HA63.48 51 6 200° C. 23% DCPA 60.89 35.618 77% HA 52 6 700° C. 8% HA 93.304.485 92% β-TCP 53 6 200° C. 27% DCPA 61.64 62.400 73% HA 54 6 600° C. -1 h 60% HA 57.41 32% β-TCP 8% β-TCPM 55 6 640° C. - 1 h HA 85.00 6.350β-TCP β-TCPM 56 6 600° C. - 1 h HA 56.32 β-TCP β-TCPM 57 6    600° C. -40 min HA 60.37 β-TCPM 58 6 200° C. 18% DCPA 58.44 82% HA 59 6 900° C. -3 h 8% β-TCP 94.03 92% HA 60 6 200° C. 45% DCPA 68.11 30.917 55% HA 61 6900° C. 15% β-TCP 92.82 85% HA 62 6 600° C. HA 67.31 β-TCP β-TCPM 63 6200° C. HA 67.31 26.070 β-TCPM 64 6 250° C. HA 64.97 23.756 β-TCPM 65 6250° C. 59% DCPA 62.55 34.131 41% HA 66 7 250° C. HA 62.00 67 6 500° C.HA 57.00 34.935 68 7.68 200° C. HA 59.71 69 7 200° C. HA 53.80 70 7 200°C. 5% DCPA 57.23 95% HA 71 10.49 250° C. HA 61.54 49.097 72 8.57 200° C.HA 65.79 73 6.59 400° C. HA 59.07 69.071 74 6.59 200° C. HA 58.43 756.59 400° C. HA 59.62 76 6.59 500° C. - 1 h HA 57.98

To prepare each of samples 1-76, two solutions of CaO in water wereprepared as discussed above. The first solution was combined with H₃PO₄solution, lowering the pH of the combined solution in steps as shown inFIG. 3. The second solution of CaO in water was then added, raising thepH of the product solution to the value shown in column 2 of Table 9.

For each of samples 1-76 in Table 9, data in the columns of the tableindicate the various reaction conditions used and product properties.The data in the “Final pH” column indicate the final pH of the productslurry after all of the Ca(OH)₂ from the second Ca(OH)₂ solution wasadded to the aqueous slurry of Ca(H₂PO₄)₂. Data in the “Heating” columnindicate the conditions of any post-isolation heat treatment of thecalcium phosphate compositions obtained, including the temperature towhich particles of the composition were heated and the duration of theheat treatment at that temperature.

Data in the “Phases” column indicates the observed phases in each of theproduct calcium phosphate compositions that were synthesized. Some ofthe compositions were observed to be monophasic, while others werebiphasic or triphasic. The percentages indicate the relative amounts ofeach phase compound in the overall composition, and the acronymsindicate the chemical nature of the phases. In each of the samples, thevarious phases were identified using x-ray diffractometry, infraredspectroscopy, and/or Raman spectroscopy. In x-ray diffractionexperiments, each of the phases generates a unique pattern of scatteringpeaks that acts as a “fingerprint” for the phase. Similarly, in bothinfrared and Raman spectroscopy, each phase generates a unique set ofpeaks that represent vibrational resonances among atoms in the phase,and similarly functions as a fingerprint for identification of thephase.

Data in the “Cryst. (%)” column indicate the percent crystallinitymeasured for each sample using x-ray diffraction techniques. Data in the“SSA (m²/g)” column correspond to measured values of specific surfacearea for the samples, in units of m²/g, measured by dry N2 adsorptionusing the BET method.

(1) Control of Calcium Phosphate Composition Phases

As is evident from the data shown in the foregoing examples, the methodsdisclosed herein provide for controlled synthesis of monophasic,biphasic, and triphasic calcium phosphate compositions. The methods alsopermit a variety of different calcium phosphate compounds to besynthesized as the constituent phases in biphasic and triphasiccompositions. Further, the methods permit the relative proportions ofthe different phases to be varied in a systematic way.

For example, samples 9, 10, 12-15, and 42-44 in Table 9 each correspondto a calcium phosphate composition formed of pure hydroxyapatite. Amongthese samples, the final pH and post-isolation heat treatment differed.However, the molar ratios of Ca²⁺ ions to H₂PO₄ ⁻ ions that were used toproduce the compositions yielded a common monophasic product, albeitwith differences in certain physical properties.

Samples 1-4 in Table 9 each correspond to a calcium phosphatecomposition formed of pure β-TCP. Among these samples as well, thepost-isolation heat treatments differed, but the molar ratios of Ca²⁺ions to H₂PO₄ ⁻ ions that were used to produce the compositions yieldeda monophasic product with the same chemical identity, and differencesonly in certain physical properties.

Biphasic calcium phosphate compositions with different phases can alsobe readily formed. For example, samples 5-7, 20, 21, 23, 25, 27, 33, 37,and 40 in Table 9 each correspond to biphasic calcium phosphatecompositions with phases of β-TCP and HA. Among these samples, theproportion of β-TCP varied from 5% to 78%, and the proportion of HAvaried from 95% to 22%. This variation in phase composition among thevarious samples was primarily due to differences in the molar ratios ofCa²⁺ ions to H₂PO₄ ⁻ ions that were used to produce the compositions.The variation was also partly attributable to post-isolation processingof the samples at elevated temperature, which tends to shift the phasecomposition of biphasic and triphasic products slightly. Based on thedata from these samples, and from the pure monophasic β-TCP and HAcompositions discussed above, biphasic calcium phosphate compositionsfeaturing phases of β-TCP and HA can be produced using the methodsdisclosed herein such that the relative proportions of β-TCP and HA canbe any amount from nearly 0% to nearly 100% in the compositions, throughsuitable variation of the molar ratios of Ca′ ions to H₂PO₄ ⁻ ions thatare used to produce the compositions, and post-isolation processing ofthe compositions at elevated temperature. Interpolating and/orextrapolating the ion molar ratios between values corresponding tospecific examples in Table 9 will nominally yield compositionsapproximating any desired phase distribution of β-TCP and HA in biphasiccalcium phosphate compositions.

Samples 30, 46, 49, 51, 53, 58, 60, 65, and 70 in Table 9 eachcorrespond to biphasic calcium phosphate compositions with phases ofDCPA and HA, where the relative proportions of each phase vary among thesamples. Among the samples, the relative proportion of DCPA varies from5% to 70%, and the relative proportion of HA varies from 95% to 30%. Aswith the biphasic β-TCP and HA compositions discussed above, therelative proportions of both DCPA and HA can be adjusted in a systematicmanner by selecting suitable values for the molar ratio of Ca′ ions toH₂PO₄ ⁻ ions that are used to produce the compositions, and for smalleradjustments, changing the post-isolation processing temperature.Interpolating and/or extrapolating the ion molar ratios between valuescorresponding to specific examples in Table 9 will nominally yieldcompositions approximating any desired phase distribution of DCPA and HAin biphasic calcium phosphate compositions, with the relative proportionof each phase in any amount from nearly 0% to nearly 100%.

Samples 19 and 22 in Table 9 correspond to biphasic calcium phosphatecompositions with phases of DCPD and HA. The relative proportions of thephases in the two samples are almost exactly opposite. Biphasiccompositions with DCPD and HA in amounts intermediate between theproportions shown in samples 19 and 22, or in amounts larger or smallerthan the proportions in the two samples, can readily be prepared byinterpolating or extrapolating the molar ratios of Ca′ ions to H₂PO₄ ⁻ions that are used to produce the compositions of samples 19 and 22 inTable 9. In this manner, biphasic compositions approximating any desiredphase distribution of DCPD and HA—from nearly 0% to nearly 100% of eachcompound—can be produced using the methods disclosed herein.

Triphasic calcium phosphate compositions with systematically varyingrelative proportions of each of three phases can also be produced usingthe methods disclosed herein. Samples 18, 26, 29, 31, 32, 34, 35 and 47in Table 9 correspond to triphasic calcium phosphate compositions withphases of DCPD, DCPA, and HA, where the relative proportions of eachphase vary among the samples. Among the various samples, the relativefraction of the DCPD phase varies from 10% to 75%, the relative fractionof the DCPA phase varies from 5% to 70%, and the relative fraction ofthe HA phase varies from 10% to 60%. Among the various samples, any ofthe three phases can be present in the largest concentration (forexample, 75% DCPD in sample 18, 70% DCPA in sample 31, and 60% HA insample 32). In addition, the relative amounts of the two minorconstituents of the composition can also be varied systematically.Comparing samples 18 and 26, for example, in which DCPD is the majorityphase, either DCPA or HA can be made the next most abundant phase.Comparing samples 35 and 47 in which DCPA is the majority phase, eitherDCPD or HA can be made the next most abundant phase. And comparingsamples 29 and 47, where HA is present at relatively high concentration,either DCPD or DCPA can be present in highest concentration.

The relative proportions of DCPD, DCPA, and HA in the triphasic calciumphosphate compositions are determined to a significant extent by themolar ratios of Ca²⁺ ions to H₂PO₄″ ions that are used to produce thecompositions. Accordingly, the relative proportions of the three phasesin the compositions can be adjusted in a systematic manner by selectingsuitable values for the molar ratios, and for smaller adjustments,changing the post-isolation processing temperature. Interpolating and/orextrapolating the ion molar ratios between values corresponding tospecific examples in Table 9 will nominally yield compositionsapproximating any desired phase distribution of DCPD, DCPA, and HA intriphasic calcium phosphate compositions, with the relative proportionof each phase in any amount from nearly 0% to nearly 100%.

(2) Control of Calcium Phosphate Composition Surface Area

The surface area of the calcium phosphate compositions producedaccording to the methods disclosed here can be controlled in variousways. The specific surface area of the compositions is directly relatedto the presence of pores and channels in particles of the compositions.In general, the larger the number of such pores and channels, the largerthe surface area of the product compositions.

The porosity, and therefore the surface area, of the compositions can beadjusted both chemically and physically. To increase the surface area ofthe compositions, the porosity of product particles can be increased bysubjecting the particles to a physical thermal shock treatment asdiscussed above, which introduces pores into the particle structure assteam is liberated from the particle interiors. Multiple thermal shocktreatments can be used to increase the porosity of the productparticles, such that the surface area of the product composition can besystematically controlled over a wide range.

The porosity and surface area of the product compositions can also becontrolled by adjusting the final pH of the product slurry, bycontrolling the amount of Ca(OH)₂ solution that is added to thedihydrogen phosphate-based intermediate species. In general,compositions formed at higher pH values have smaller pores and smalleraggregate surface area. Adjusting the slurry pH by changing the amountof Ca(OH)₂ solution that is added provides a chemical method forcontrolling the specific surface area of the product compositions.

As evidenced by the examples disclosed herein, compositions with a widerange of specific surface areas can be produced using the above methods.In some embodiments, for example, the surface area of a calciumphosphate composition produced as disclosed herein is 30 m²/g or more(e.g., 40 m²/g or more, 50 m²/g or more, 60 m²/g or more, 70 m²/g ormore, 80 m²/g or more, 85 m²/g or more, 90 m²/g or more).

Compositions with a wide range of specific porosities can also beproduced. In certain embodiments, for example, the porosity of a calciumphosphate composition produced as disclosed herein is 20 cm³/g or more(e.g., 25 cm³/g or more, 30 cm³/g or more, 35 cm³/g or more, 40 cm³/g ormore, 45 cm³/g or more, 50 cm³/g or more, or even more).

(3) Control of Calcium Phosphate Composition Crystallinity

The methods disclosed herein can be used to produce a variety ofdifferent monophasic, biphasic, and triphasic calcium phosphatecompositions with systemically controlled crystallinity. In general, thecrystallinity of the product composition depends upon the chemicalnature of the composition, the post-isolation processing temperature (ifany), and the post-isolation processing time. Typically, as thepost-isolation processing temperature increases, the productcomposition's crystallinity increases. Similarly, as the processing timeincreases, the composition's crystallinity increases.

The samples in Table 9 demonstrate control and selectivity overcrystallinity for a variety of different products. For example, samples1-4 correspond to a monophasic calcium compositions formed from pureβ-TCP. By increasing the post-isolation processing temperature and time,the crystallinity of the products can be varied from 96.35% to 99.30%.

Similarly, samples 9, 10, and 12-14 correspond to monophasic calciumphosphate compositions formed from pure HA. Among the samples,increasing the post-isolation processing temperature and time changesthe product crystallinity in a systematic manner from 49.94% to 91.48%.

The product crystallinity can also be systematically adjusted throughcontrol of the post-isolation processing temperature and time formultiphasic product compositions. Samples 5-8 and 39 correspond tobiphasic product compositions with phases of β-TCP and HA. Thecrystallinity of these samples is varied in a controlled manner from78.31% to 96.74%.

For biphasic and triphasic product compositions, the same generalprinciple applies—increasing the post-isolation processing temperatureand processing time typically results in increased crystallinity in theproduct. However, in these more complex compositions, the crystallinityof the product also depends on the relative proportions of the variousphases present and the chemical nature of those phases. In addition,post-isolation heating can modify the chemical nature and relativeproportions of the phases present in the composition. Thus, for example,samples 26, 34, and 35 each correspond to triphasic compositions withphases of DCPD, HA, and DCPA. In sample 26, processed at 200° C., theratio of DCPD:HA:DCPA was 60:30:10, and the crystallinity was 40.46% Insample 34, processed at 200° C., the ratio of DCPD:HA:DCPA was 60:15:25,and the crystallinity was 74.80%. In sample 35, processed at 250° C.,the ratio of DCPD:HA:DCPA was 50:20:30, and the crystallinity was66.01%. Comparing samples 26 and 34, the relative fraction of HA in theproduct composition decreased and the fraction of DCPA increased,leading to an increase in the product's crystallinity. Comparing samples34 and 35, in sample 35 the relative fraction of HA in the productcomposition increased in relation to sample 34 while the relativefraction of DCPD was reduced. The crystallinity of sample 35 wastherefore reduced in relation to sample 34, even though sample 35 wasprocessed at a slightly higher temperature.

All other factors being equal, increasing the post-isolation processingtemperature and processing time yields product compositions with highercrystallinity, and by interpolating between, and extrapolating from,processing conditions for the samples shown in Table 6, products withdesired levels of crystallinity can be obtained for a wide variety ofmonophasic, biphasic, and triphasic product compositions. In general,the crystallinity for calcium phosphate compositions produced accordingto the methods disclosed herein can be 40% or greater (e.g., 50% orgreater, 60% or greater, 70% or greater, 80% or greater, 90% or greater,95% or greater, 98% or greater, 99% or greater, 99.5% or greater).

(4) Control of Calcium Phosphate Composition Particle Size/Aspect Ratio

The methods disclosed herein can be used to produce calcium phosphatecompositions formed of nanometer-sized individual particles of highaspect ratio. Nanometer-sized particles can be advantageous for a numberof applications in which the particles act as hosts for other chemicalagents, and decompose when injected or otherwise introduced into aliving organism. By producing particles with a controlled range of sizesin the nanometer regime, the in vivo decomposition rate of the particlescan be controlled. Further, high aspect ratio calcium phosphateparticles are advantageous because the particles flow more easilythrough body lumens than bulkier particles of smaller aspect ratio. Assuch, they can be better suited to certain in vivo applications thanother lower aspect ratio particles.

In particular, high aspect ratio calcium phosphate particles have shapesthat are similar to the natural morphology of certain calcium phosphatesin biological structures such as teeth and bone. As such, the highaspect ratio particles have advantageous biomimetic properties, and canbe used as replacements for the naturally occurring calcium phosphatecompounds. The properties of the high aspect ratio particles mimic theproperties of their naturally occurring counterparts in biologicalstructures. In particular, the high aspect ratio shape yields particleswith particular ranges of porosity such that organic material in bloodand other body fluids can penetrate the particles, while at the sametime, the particles provide a suitably dense scaffold for cellularregeneration and growth. As such, the high aspect ratio calciumphosphate particles produced as disclosed herein are particularly usefulfor applications in which bio-integration is a significantconsideration.

Particles of the calcium phosphate compositions disclosed herein arecharacterized by their maximum dimension, which corresponds to thelargest linear distance between any two points on the particle surface,as measured in a two dimensional image of the particle. Examples of SEMimages of particles of some of the samples described herein are shown inFIGS. 8A-8C, 9A-9B, and 10A-10B. In these figures, the particles areformed as tiny crystallites with generally elongated shapes. In general,particles of the calcium phosphate compositions prepared according tothe methods disclosed herein can have an average maximum dimension ofbetween 100 nm and 500 nm (e.g., between 100 nm and 400 nm, between 100nm and 300 nm, between 150 nm and 400 nm, between 150 nm and 300 nm,between 175 nm and 400 nm, between 175 nm and 300 nm, between 200 nm and400 nm).

The aspect ratio of a particle is the ratio of the particle's maximumdimension (measured as discussed above) to its largest dimension in adirection orthogonal to the maximum dimension in the plane of a twodimensional image of the particle. Like the maximum particle dimension,a particle's aspect ratio can be determined from an image of theparticle such as an SEM image. As shown in FIGS. 8A-8C, 9A-9B, and10A-10B, the methods disclosed herein can be used to produce particlecompositions in which the average aspect ratio for the particles isrelatively larger. For example, particles of the calcium phosphatecompositions prepared according to the methods disclosed herein can anaverage aspect ratio of 50:1 or more (e.g., 75:1 or more, 100:1 or more,150:1 or more, 200:1 or more, 250:1 or more, 300:1 or more).Post-isolation processing at elevated temperature typically yieldshigher aspect ratio particles. By increasing the temperature and/or theprocessing time, particle compositions with higher average aspect ratioscan be produced.

OTHER EMBODIMENTS

A number of embodiments have been described. Nevertheless, it will beunderstood that various modifications may be made without departing fromthe spirit and scope of the disclosure. Accordingly, other embodimentsare within the scope of the following claims.

What is claimed is:
 1. A composition, comprising: a material comprisingthree calcium phosphate phases that form one or more integral units of asolid, wherein a first one of the three phases comprises one or moreregions formed of hydroxyapatite; wherein a second one of the threephases comprises one or more regions formed of β-tricalcium phosphate;wherein a third one of the three phases comprises one or more regionsformed of amorphous calcium phosphate; and wherein at least some of theregions corresponding to the first, second, and third phases contact oneanother in the one or more integral units of the solid.